Regulations of hpa by cytokines

Addis Ababa University

School of health sciences

Department of physiology

Regulation of the Hypothalamic-Pituitary-Adrenal Axis

by Cytokines: Actions and Mechanisms

A Review

By

Girmay Fitiwi

April, 2012

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Acknowledgments

I would like to extend my deepest gratitude and appreciation to my advisor Dr. Getahun Shibru

for his excellent valuable, careful reviewing and scientific comments of the manuscript. I also

thank AAU digital libraries for their full resources of journals and free internet access.

Finally I would like to thank to my instructors, my family and my colleagues.

II | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s

Table of Contents

Contents Page

Acknowledgments ......................................................................................................... I

Table of Contents ........................................................................................................ II

List of Acronyms ........................................................................................................ IV

List of Figures ........................................................................................................... VII

Summary ................................................................................................................. VIII

1. Introduction ............................................................................................................... 1

2. Over View of Cytokines ............................................................................................ 2

2.1. IL-1, IL-6, and TNF ..................................................................................... 7

3. Hypothalamic-pituitary-adrenal axis ....................................................................... 9

4. Cytokines Effect on the Secretory Activities of HPA axis ..................................... 11

5. Cytokine Actions on the Central Nervous System, Pituitary, and Adrenal .......... 12

6. Evidence that Cytokines Activate the Hypothalamic-Pituitary-Adrenal Axis

Primarily at the Level of the Central Nervous System ........................................... 13

6.1 Cytokine receptors within the CNS .............................................................. 13

6.1.1. IL-1 Receptors in the CNS ........................................................ 14

6.1.2. IL-6 Receptors in the CNS ........................................................ 15

6.1.3. TNF Receptors in the CNS ....................................................... 16

6.2. Cytokine Expression in the CNS .................................................................... 17

6.2.1. Basal Expression ........................................................................ 17

6.2.2 Induced Expression ...................................................................... 18

6.3. Cytokine Actions at the Level of the CNS ...................................................... 20

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7. Evidence for Direct Effects of Cytokines Pituitary Adrenocorticotropic

Hormone Secretion ................................................................................................. 22

7.1. Cytokine Receptors within the Pituitary ...................................................... 22

7.2. Cytokine Expression in the Pituitary ........................................................... 23

7.3. Direct Effects of Cytokines on Pituitary ACTH ........................................... 24

8. Evidence for Direct Actions of Cytokines on Adrenal Glucocorticoids

Secretion ................................................................................................................. 25

8.1. Cytokine Expression in the Adrenal Gland .................................................. 25

8.2. Direct effects of cytokines on Adrenal Glucocorticoids Secretion ............... 26

9. Mechanisms OF Hypothalamic Pituitary Adrenal Axis Activation by

Interleukin-1 ........................................................................................................ 27

9.1. Direct Actions of IL-1 on Pituitary and Adrenal .......................................... 28

9.2. Penetration of Cytokines into Brain............................................................. 29

9.3. Cytokines and Blood-Brain Barrier Integrity ............................................... 31

9.4. Carrier-Mediated Transport of Cytokines across the Blood-Brain Barrier .... 31

9.5. Role of Readily Diffusible Intermediates .................................................... 32

9.6. Cytokines Actions at Circumventricular Organs .......................................... 32

10. Conclusions and prospective Studies ................................................................... 33

11. References

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List of Acronyms

ACTH Adrenocorticotropin hormone

aFGF acidic fibroblast growth factor

AP Area Postrema

AV3V Antero Ventricular Third Ventricle

AVP Arginine Vasopressin

BBB Blood Brain Barrier

BDNF Brain-derived neurotrophic factor

bFGF basic fibroblast growth factor

CAMP Cyclic Adenomono Phosphate

Cinc cytokine-induced neutrophil chemo attractant

CNS Central Nervous System

CNTF Ciliary Neurotropic Factor

CRH corticotropic releasing factor/hormone

CSF Colony Stimulating Factor

CT-1 Cardiotropin1

CVO Circumventricular organs

EGF Epidermal Growth Factor

GC Glucocorticosteroids

G-CSF Granulocyte Colony Stimulating Factor

GDNF Glial Derived Neurotrophic Factor

GM-CSF Granulocyte-Macrophage Colony Stimulating Factor

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gp130 Glyco protein 130

gro Growth-Related Oncogene

HPA Hypothalamic pituitary adrenal

IH Inferior Hypophysial

ICE Interleukin Converting Enzyme

IFN-α/ β/ γ Interferon alpha/beta/gamma

IGF insulin-like growth factor

IL Interleukin

IL-1R1/ IL-1R2 interleukin receptor1/2

IL-Ira Interleukin-1 receptor antagonist

IP Intraperitoneal

IV Intravenous

JAK Janus kinase

LIF Leukemia Inhibitory Factor

LPs Lipopolysaccharides

MCSF Macrophage Colony Stimulating Factor

ME Median Eminence

MIF Macrophage migrating inhibitory factor (MIF)

MIP Macrophage inflammatory protein

mRNA Messenger Ribonucleic Acid

NAP Neutrophil Activating Protein

NFkB Nuclear factor KB

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NGF Nerve Growth Factor

NT Neurotrophin

OM Oncostatin M

OVLT Organum Vascularis Lateral Terminalis

PACPA Pituitary Adenylate Cyclase Activating Polypeptide

PCR Polymerization Chain Reaction

PDGF Platelet-Derived Growth Factor

POMC proopiomelanocortin

PVN paraventricular nucleus

RANTES Regulated upon activation Normal and Secreted

RNA Ribo Nucleic Acid

SH Superior Hypophysial

SCF Stem Cell Factor

SFO Subfornical organ

STAT Signal transducer and activator of transcription protein

TGF Transforming Growth Factor

TNFR1/R2 Tumor Necrosis Factor Receptor1/2

TNF-α/ β Tumor Necrosis Factor alpha/beta

VIP Vasoactive Intestinal Peptide

VII | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s

List of Figures

Figure 1. Reciprocal Relationship between the CNS and Immune System…….1

Figure 2. Cytokines Family………6

Figure 3. Functional Anatomy of Hypothalamic-Pituitary-Adrenal Axis …….10

Figure 4. Proposed models by which interleukin-1 influences secretory activity of hypothalamic

Pituitary- Adrenal Axis….30

List of Tables

Table 1. Cytokines Family……5

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Summary

Cytokines are low molecular, soluble glycoprotein intracellular mediators produced ubiquitous-

ly during inflammation, infection, psychological and physical stress to maintain homeostasis

mechanisms of the body by coordinating neuroendocrine immune system. Furthermore cytokines

are not only important during threating conditions, but also important in normal physiological

process such as in sleep, exercise and ovulation in very low concentration.

Several cytokine families increase the secretory activity of the HPA axis. Constitutive expression

of cytokines, even though at low levels, has been reported also on most cell types throughout the

brain and in the hypothalamus-pituitary-adrenal (HPA) axis, and these often show rapid up-

regulation in response to injury and inflammation. In rodent brain tissues, the highest densities

of cytokine receptors occur in the hippocampus and hypothalamus. Cytokine receptors are also

widely expressed within anterior pituitary cells.

Almost all proinflammatory cytokines stimulate the HPA axis in vivo and proopiomelanocortin

(POMC) expression in vitro. HPA stimulation occurs either at the hypothalamic level (IL-1β, TN

F α), inducing CRH gene expression and CRH release or at the level of pituitary corticotrophs.

In addition to CRH, inflammatory cytokines also trigger central ACTH secretagogues such as

noradrenaline, pituitary adenylate cyclase-activating polypeptide (PACAP), vasopressin and

other cytokines. Proinflammatory cytokines may impair feedback regulation of the HPA axis by

attenuating glucocorticoids receptor function. By stimulating the HPA axis and release of ant-

inflammatory glucocorticoids, cytokines can antagonize their own proinflammatory action.

Key words: adrenal gland: anti inflammatory: blood brain barrier (BBB): central nervous sys-

tem: circum ventricular organs: cytokines: interleukins: proinflammatory: lipopolysaccharides:

paraventricular: pituitary.

1 | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s

1. Introduction

The nervous, endocrine and immune systems are anatomically and functionally interconnected.

These organ systems both express and respond to a large number of common regulatory mole-

cules including steroids, neuropeptide, cytokines and neurotransmitters, which provide the mo-

lecular basis for integrated, bidirectional coordinated neuroendocrine-immune responses to ho-

meostasis disturbances induced by stress, inflammation or infection. By the 1980s, the immune

system was known to synthesize and secrete a number of chemical messengers, which were

known generically as cytokines (Besedovsky et al., 1986, Turnbull and Catherine, 1999).

Cytokines are low molecular-weight proteins or glycoproteins that were initially thought to be

restricted to the immune system as mediators of communication between immune cells. Howev-

er, it soon becomes evident that cytokines exert profound effect on the key functions of the cen-

tral nervous, such as food intake, fever, neuroendocrine regulation, long-term potentiation and

behavior. It was reported that cytokines were also produced by brain cells and that they interact

closely with neurohormones and neurotransmitters. Furthermore the regulatory pathways that

control the immune system include the autonomic nervous system and neuro endocrine hor-

mones such as CRH and substance P (Ziemssen and kern, 2007).

FIG.1 Reciprocal Relationship between the CNS and Immune System (source: John Haddad et al., 2002)


This paper attempts to review the role of cytokines in regulation of hypothalamic pituitary adren-

al axis, briefly on the effects of cytokine on hypothalamic neurons, which have response for se-

cretion of CRH, on the adenohypophysis of Pars dsitalis related to ACTH and the direct effect on

adrenal cortex.

2. Over View of Cytokines

Cytokines are a diverse group of pleiotropic1 and redundant

2 soluble polypeptides that are rapid-

ly produced by immune cells in response to tissue injury, infection or inflammation. Furthermore

it mediates growth, differentiation and function of many different cell types (Turnbull and

Rivier, 1999). Constitutive expression of cytokines, even though at low levels, has been report-

ed also on most cell types throughout the brain and in the hypothalamus-pituitary-adrenal (HPA)

axis, and these often show rapid up-regulation in response to injury and inflammation (Anastasia

et al., 2004) . In rodent brain tissues, the highest densities of cytokine receptors occur in the hip-

pocampus and hypothalamus (Vitkovic et al., 2000). Cytokine receptors are also widely ex-

pressed within anterior pituitary cells (Ray and Melmed, 1997, Turnbull and Rivier, 1999).

The classification of cytokines into families has proven somewhat arbitrary. With the exception

of a few homologous peptides (e.g., IL-1α and 1β; interferon α and β; and tumor necrosis factor,

α, β) most cytokines share little sequence similarity. Consequently, classification of cytokines

has been based on functional attributes, target receptors, or cells of origin. Most commonly cyto-

kines have been classified into families of interleukins 1 to 13 (IL-1 to -13), tumor necrosis fac-

tor α and β, transforming growth factor β, interferon α, β, and γ, chemokines, hematopoietins (or

neuropoietins) and colony-stimulating factor. Growth factor and neutrotropins are categorized as

cytokines because of their similar action particularly within central nervous and peripheral nerv-

ous system. All of these factors are polypeptides and act on a variety of target cells through spe-

cific plasma membrane receptor proteins in a non-antigen-specific manner and a typical action is

defined as autocrine or paracrine, but not commonly considered endocrine (Simon et al., 1994).

1 Any given cytokine may have different biological effect on different target cells.

2 Two or more cytokine may mediate similar functions.


One of the striking futures of cytokines is pleiotropy and redundancy (Cohen MC and Cohen S,

1996). Cytokine pleiotropy presumably relates to the wide spread distribution of cytokine recep-

tors on numerous cell types and their ability of signal transduction mechanisms activated by cy-

tokines to alter the expression of a wide variety of target genes. The functional redundancy of

various cytokines has at least partially been explained by the identification and molecular clon-

ing of many cytokine receptors. Some, although certainly not all, cytokine receptors consist of a

multiunit complex, including a cytokine-specific ligand binding component and a class specific

signal transduction unit (kishimoto et al.,1995, Sato and Miyajim,1994). In addition to the gp130

signaling cytokines, common receptor subunits have also been demonstrated for IL-2, IL-4, and

IL-7 (Sato and Miyajima,1994) and also for IL-3, IL-5, and granulocyte-macrophage CSF which

share the signal transduction subunit KH7 (Miyajima et al.,1992). However, cytokine redundan-

cy cannot be totally explained by the sharing of receptor subunits, since a number of cytokines,

for example, IL-1, IL-6, and TNF-α, have many common biological activities despite the utiliza-

tion of distinct cell surface receptors.

A further striking feature of cytokines is the multiple interactions between different individual

cytokines. Many types of interactions are apparent, including stimulatory or inhibitory actions at

the level of cytokine synthesis. For example, the proinflammatory cytokines TNF-α and IL-1

potently stimulate the production of a number of other cytokines, including each other, as well as

IL-6, IL8, IL-9, macrophage inflammatory protein (MIP), and CSF (Dinarello,1991). In contrast,

anti-inflammatory cytokines such as IL-4, IL-10, and IL-13 abrogate the production of many

proinflammatory cytokines (e.g., IL-1, IL-8, IL-12, TNF α, IFN γ, and CSF) (Burger and Dayer,

1995). The great prosperity for cytokine-cytokine interactions is illustrated by the large number

of different cytokines that may be produced by a single threat to cellular/ tissue homeostasis. For

example, endotoxemia has been reported to cause the increased synthesis and secretion of IL-1a,

IL-1b, IL-1ra, IL-6, IL-8, IL-10, IL-12 TNF α, MIP, macrophage migrating inhibitory factor

(MIF), IFN γ, leukemia inhibitory factor (LIF), and granulocyte-macrophage and CSF. It is

therefore apparent that during the course of a threat to tissue homeostasis, the physiological out-

come is determined by the net effect of the interactions between a numbers of cytokines.


Cytokines may play a role in some physiological processes in very low concentration such as in

sleep (Szafarczyk et al., 1988) exercise (Cannon and Dinarello, 1985) and ovulation (Adashi,

1997). However cytokine production increases markedly during tissue stress produced by diverse

cellular challenges, including periods of rapid cellular growth, tissue remodeling, disease, infec-

tion, or trauma. The particular cytokines produced in response to a threat to tissue homeostasis

depends on the nature of the threat (e.g., bacterial, viral, inflammatory), the cellular or tissue type

being threatened, the hormone milieu, and to a large extent the profile of other cytokines that are

being produced.


Table1. Cytokines Family (Source: Younis and Abou El-Ezz, 2010)

Family Members Major ascribed actions

Interleukins Il-1 to IL-18 Categorization as an IL does not im-

ply function; IL have numerous and diverse Immuno regulatory actions;

some IL have clearly

proinflammatory actions (e.g., IL-1a, IL-1b, IL-8, IL-9), whereas others

have anti-inflammatory effects (e.g.,

IL-1ra, IL-4, IL-10, IL-13). Many IL

also induce systemic aspects of acute phase response (e.g., fever)

Tumor necrosis factor TNF α, TNF β Tumor cytotoxicity; broad-ranging

immunologic activities; induction of many other cytokines ,

immunostimulant , proximal mediator

of inflammatory response

Interferon IFN α,β,γ Inhibit viral replication; regulation of specificity of immune responses

Chemokines IL-8/cinc/gro/NAP-1,

MIP-1a,-b,RANTES

Chemotaxis; activation of cells at in-

flammatory sites

Hematopoietins IL-6,CNTF,LIF,OM,IL-

11,CT-1 All Utilize gp 130 receptor subunit

for signaling; various action on B

cells and other immuno regulatory actions; promote survival of neurons

Colony stimulating factors G-CSF,M-CSF,GM-CSF,

SCF,Il-3,IL-5

Promotion of growth and differentia-

tion of multi potential progenitor cells

in bone marrow; increase numbers of, or enhance activity of, cells of granu-

locyte, macrophage, and eosinophil

lineages

Neurotrophins NGF,BDNF,GDNF,NT-

3,NT-6 Neuronal growth and differentiation

Growth Factors IGFI,IGFII,aFGF,bFGF,PD

GF,TNF β, activin Cell growth and differentiation


FIG.2 Cytokines Family (Source: Younis and Abou El-Ezz, 2010)

Although many different cytokines have been shown to influence HPA axis secretory activity, by

far the majority of studies have focused on the cytokines IL-1, IL-6 and TNFα herein, gives a

brief discussion on the structure, biosynthesis, and receptors of these three cytokines.

Cytokines

Anti-inflammatory cytokines

Up-regulation of the in-

flammatory response

IL-1

IL-6

TNF-a

IFN-a

IFN-b

Up-regulation of acute

phase reactants

IL-1

IL-6

IL-11

TNF-α

IFN-γ

TNF-β

Inhibition of pro-

inflammatory cytokines

IL-1

IL-6

IL-13

Inhibition of NO syn-

thase activity

IL-10

Pro-Inflammatory cytokines

Stimulation of pro-

inflammatory cytokines

IL-12

Chemoattractant IL 8 TGF-β inhibits T cell

proliferation, enhances

collagen production and

facilitates the isolation of

the inflammatory focus


2.1. IL-1, IL-6, and TNF

Interleukin -1 is the prototype of the pro-inflammatory cytokines in that it induces the expression

of a variety of genes and the synthesis of several proteins that, in turn, induce acute and chronic

inflammatory changes. IL-1 is also the prototypic alarm cytokine in that it brings about increases

in a variety of defense mechanisms (Dinarello, 1991).

There are three distinct glycoproteins that constitute the IL-1 family. The two agonists (IL-1a,

IL-1b) and an endogenous antagonist at IL-1 receptors (IL-1ra). IL-1a and IL-1b share 25% se-

quence homology, are distinct gene products, and exhibit the same activities in numerous bio-

logical test systems (Dinarello, 1991). Both are synthesized as 31-kDa3 precursor molecules.

Pro-IL-1b is biologically inactive and requires proteolytic cleavage by the IL-1b converting en-

zyme (ICE, also known as caspase-1) (Keane et al., 1993). In addition an endogenous antagonist

at IL-1 receptors (IL-1ra) shares significant homology with IL- 1a and IL-1b, binds IL-1 recep-

tors, but lacks intrinsic biological activity (Hannum et al., 1990).

The IL-1 receptor is expressed in most cells and tissues, although often at very low levels (<100

binding sites per cell).There are two distinct mammalian membrane-bound IL-1 receptors, desig-

nated IL-1R1 and IL-1R2 and one receptor accessory protein (Greenfeder et al., 1991). Both re-

ceptors are glycoproteins belonging to the immunoglobulin supergene family and possess a sin-

gle transmembrane domain. Each receptor binds IL-1a, IL- 1b, and IL-1ra, but with differing af-

finities. It has been proposed that the biological actions of IL-1 are mediated exclusively through

IL-1R1 (Labow et al., 1997), with IL-1R2 functioning solely as a decoy receptor that limits the

availability of IL-1 for interaction with IL-1R1 (Colotta et al., 1993).

3 A unit that is used for indicating mass on atomic or molecular scale. It is defined as one twelfth

of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground

state and has a value of 1.660 538 921(73) x 10-27

Kg.


Tumor necrosis factor occurs in α and β forms, which share approximately 50% homology.

TNFα (also known as cachectin) is expressed on a wide variety of hemopoietic and non

hemopoietic cells as a 26-kDa membrane-associated molecule. This can be processed to give a

secreted 17-kDa soluble form that mediates a range of inflammatory and cellular immune re-

sponses.

Actions of TNFα are exerted through interactions with two distinct receptors: the 55-kDa (TNF-

R1) and 75- kDa (TNF-R2) receptors. These two receptors are both transmembrane proteins with

a single transmembrane span and are expressed at low levels on most cell types. Although the

extracellular domains of these two receptors show a similar architecture, the intracellular do-

mains of these two receptors bear no significant homology, suggesting that they utilize separate

signaling path ways (Lewis et al., 1991).

Binding of TNF to either receptor activates the proinflammatory transcription factor NFkB. In

the case of TNF-R2, signal transduction occurs via heteterodimerization of the receptor with two

TNF-R2 associated factors, TRAF1 and TRAF2, and it is TRAF2 that appears to mediate TNF-

R2-induced activation of NFkB. In contrast, TNF-R1, upon ligand binding recruits a protein

called TRADD, which causes apoptosis via an ICE-like protease. This explains why TNF-R1,

but not TNF-R2, causes apoptosis. However, the NH2-terminal domain of TRADD interacts di-

rectly with TRAF2, and over expression of a dominant negative TRAF2 blocks not only TNF-R2

but also TNF-R1-induced NFkB activation. Thus activation of the two TNF receptors elicits sep-

arate signaling pathways that can interact with one another, thus explaining the distinct and over-

lapping signals generated by the two TNF receptors. Tumor necrosis factor β (lymphotoxinα) is

produced predominantly by activated lymphocytes.

Interleukin-6 is a single 21 to 28kDa glycoprotein produced by both lymphoid and non lymphoid

cells and regulates immune responses, acute-phase protein synthesis, and hematopoiesis. Human

IL-6 is synthesized as a precursor polypeptide of 212 amino acids that is processed by cleavage

of a 28amino acid NH2-terminal signal sequence into a mature form of 184 amino acids (Turn-

bull and Catherine, 1999).

Interleukin-6 belongs to a family of cytokines that includes ciliary neurotropic factor (CNTF),

oncostatin M (OM), LIF, IL-11, and cardiotropin1 (CT-1), which shares a common signal-


transducing mechanism (Kishimoto et al., 1995). All these cytokines are bound by receptors that

interact with the common cell-surface protein gp130. Ligand-receptor complexes that share

gp1304 trigger signaling by the formation of either homodimers of gp130 or hetero dimers be-

tween gp130 and LIFR. Regarding IL-6, signaling is initiated by the homodimerization of gp130

induced by the interaction with the IL-6/IL-6Rα complex. Either homodimerization of gp130 or

heterodimerization of gp130 with LIFR activates JAK kinases, followed by the tyrosine-specific

phosphorylation and nuclear translocation of a member of the STAT family (STAT3) of tran-

scription factors and finally elicit a cellular response (Turnbull and Rivier, 1999).

3. Hypothalamic-Pituitary-Adrenal Axis

The HPA axis is a feedback loop including the hypothalamus, pituitary and adrenal glands, regu-

latory neural inputs and a variety of releasing factors and hormones (Daban, 2005).

The primary CNS nucleus involved in the regulation of pituitary-adrenal axis is the

paraventricular nucleus (PVN) of the hypothalamus. The PVN is the principal CNS source of the

41-amino acid peptide CRH, which is the regulator of pituitary ACTH secretion (Rivier and

Plotsky, 1986).

The CRH from the paraventricular nucleus project to the median eminence and joined to

hypophysial portal vessels finally reach at the anterior pituitary. Within the anterior pituitary,

CRH interacts with specific G protein-coupled receptor (CRF-R1) on the corticotrope cell sur-

face, resulting in the stimulation of the synthesis of the ACTH precursor peptide

proopiomelanocortin (POMC) and the secretion of ACTH and other POMC-derived peptides

(Turnbull and Rivier, 1997).

Adrenocorticotropin hormone potently induces the secretion of GC from the zona fasciculata of

the adrenal cortex. In humans, the major GC is cortisol, but in the rat Corticosterone is the main

steroid product of the zona fasciculata. In a classical endocrine feedback manner, these steroids

inhibit the synthesis and secretion of CRF within the hypothalamus and POMC-derived peptides

4 Gp130 is a transmembrane protein which is the founding member of the class of all cytokine

receptors. It forms one sub unit of type 1cytokine receptors within the IL-6 receptor family.


in the pituitary (Keller and Dallman, 1984). Furthermore, the regulation of GC is subject to di-

verse sensory inputs and this information is integrated at the level of the hypothalamus. Small

deviations from normal circulating levels of these steroids produce changes in a wide variety of

physiological and biochemical parameters (Turnbull and Rivier, 1997).

Glucocorticoids act on multiple targets to enhance or inhibit various cellular activities, actions

that are aimed at providing the altered metabolic, endocrine, nervous, cardiovascular, and immu-

nologic needs that promote survival. In addition to secretions of glucocorticoids peak during

awakening time and nadir during the first few hours of sleep.

FIG.3 Functional Anatomy of Hypothalamic-Pituitary-Adrenal Axis (source: Turnball and Rivier, 1999)


4. Cytokines Effect on the Secretory Activities of HPA axis

As this mentioned in the introductory part of this review the bicommunication between the cen-

tral nervous system and immune system is very crucial to maintain homeostasis during threaten-

ing conditions.

The first demonstration of a possible link between the immune system and the hypothalamic-

pituitary-adrenal (HPA) axis came from the report that rats injected with sheep red blood cells

showed increases in plasma corticosterone levels that paralleled their immune response

(Besedovsky et al., 1975) This led to the proposal that activated immune cells released signals,

which stimulate the activity of the HPA axis. Thereafter numerous studies have confirmed and

extended the original findings that the administration of either IL-1α or IL-1β to rats or mice,

chickens (Wick et al.,1993), sheep (Vellucci et al.,1995), baboons (Reyes and Coe,1996 ) and

humans stimulates ACTH and GC secretion as well as many other indices of HPA.

In mammals, the ACTH response to intravenous IL-1 is usually prompt, commencing within 5–

10 min, and of relatively short duration (approximately 1hour). In comparison, the plasma ACTH

response to intraperitoneal injection of IL- 1β is slower in onset, but usually of longer duration

(at least 2h). Finally the response to IL-1 administered directly into the brain

(intracerebroventricularly) is of intermediate latency and lasts for several hours (>3-4 h). The

majority of studies have found IL-1β to be more potent than IL-1α in the rat (Matta et al., 1993,

Rivier et al., 1989).

A single administration of IL-1β not only acutely elevates plasma ACTH and corticosterone con-

centrations in the rat, but has been demonstrated to produce a long lasting (at least 3 wk) in-

crease in the co expression of AVP in hypothalamic CRF neurons and a hyperresponsiveness of

the HPA axis (Schmidt et al., 1995). Long-term administration of IL-1β to rats enhances CRF

and ACTH-like immunoreactivity in the hypothalamus and pituitary, respectively, increases Ad-

renal weight (Naito et al., 1989), and elevates plasma ACTH concentration for at least 7 days

(Van Der Meer et al., 1996).


In addition to the numerous studies of the effects of cytokines on the HPA axis of laboratory an-

imals, the clinical trials of a number of cytokines as anticancer strategies have afforded the op-

portunity to detail their effects on the HPA axis of humans. Such clinical studies have permitted

investigation of the effects of cytokines on the HPA axis in a homologous system (i.e. human

cytokines in human subjects). Either intravenous or subcutaneous administration of IL-1α (Curti

et al.,1996, Smith et al.,1992), IL-1β (Crown et al.,1991), IL-2 (Atkins et al.,1986, Denicoff et

al.,1989), IL-6, TNF-α and IFN-α (Gisslinger et al.,1993), IFN-β and IFN-γ elevates plasma

ACTH and/ or cortisol concentrations.

A series of experiments in which cancer patients of good clinical performances were examined

showed that IL-6 is a particularly potent activator of the HPA axis and that the human HPA axis

is remarkably responsive to this cytokine. On the first treatment day, IL- 6 (30 mg/kg sc) induced

marked elevations in plasma ACTH and cortisol concentrations, with peaks occurring at 1 and 2

hour respectively. Plasma ACTH concentrations returned to basal levels within 5 hours, whereas

plasma cortisol levels remained elevated for 24 h. By the seventh day of treatment, the ACTH

response to IL-6 was markedly diminished an effect that was probably due to increased negative

feedback produced by persistently elevated plasma cortisol levels. The sustained secretory activi-

ty of the adrenal gland was accompanied by gross enlargement of the adrenal glands as assessed

by computed tomographic scans (Mastorakos et al., 1993).

Overall, human and animal studies agree that many exogenously administered cytokines have

marked stimulatory actions on HPA axis secretory activity and suggest that endogenous produc-

tion of cytokines during homeostatic threats may well play a causal role in the elaboration of the

accompanying HPA axis response (Turnbull and Rivier, 1997).

5. Cytokine Actions on the Central Nervous System, Pituitary and Adrenal

The effects of both administrations of cytokines to normal, healthy subjects and the consequenc-

es of inhibiting cytokine action during infectious, inflammatory, or stressful threats imply that

cytokines may play a physiological role in the regulation of the secretory activity of the HPA ax-

is. However, cytokines also produce a number of systemic acute phase responses that themselves

could elicit HPA activation, here in we can raise the question of whether the effects of cytokines


on HPA axis secretory activity are direct or secondary to stress produced by other acute phase

responses. For example, IL-1β causes fever, sickness behavior, increases in heart rate, increased

blood flow to certain vascular beds, activation of the sympathetic nervous system, and changes in

intermediary metabolism. These physiological changes are themselves challenges to the mainte-

nance of homeostasis, and each could, if pronounced, activate secretion by the HPA axis (Turn-

bull and Rivier, 1999).

The effects of some cytokines on plasma ACTH concentrations have nevertheless been dissoci-

ated from a number of these other acute phase responses. For example, IL-1 induced activation

of the HPA axis of mice kept at an ambient temperature that did not result in these animals

mounting a febrile response (Besedovsky et al., 1986). Indeed, IL-1β analogs with markedly re-

duced pyrogenicity still stimulate ACTH secretion (Besedovsky et al., 1986). In addition, en-

hanced ACTH secretion is observed after peripheral administration of IL-1β at doses that have

no or only modest effects on the secretion of other hormones, such as luteinizing hormone,

catecholamines, and prolactin, whose secretion is markedly altered by many other types of

stressors (Rivier et al., 1989, Turnbull and Rivier, 1997). Similarly, doses of IL-6 that markedly

elevate plasma ACTH and cortisol concentrations in humans have only moderate effects on other

acute phase responses (Mastorakos et al., 1993).

The influence of IL-1 on pituitary ACTH secretion was attributable to actions either at the level

of hypothalamic CRF release or directly on the pituitary itself to stimulate ACTH secretion. Fur-

thermore, cytokines may act on the adrenal glands directly (Berkenbosch et al., 1987).

The following sections describe the evidence that indicates the potential site(s) of cytokine action

on HPA axis secretory activity

6. Evidence That Cytokines Activate the Hypothalamic-Pituitary-Adrenal Ax-

is Primarily at the Level of the Central Nervous System

6.1. Cytokine receptors within the CNS

Receptors of many cytokines have been localized within the CNS or described in primary cell

cultures or cell lines derived from brain tissue. These include receptors for IL-1, IL-2, IL-3, IL-4,

IL-6, IL-7, interferon, TNF, growth factor, CSF and neutrophins (Hopkins et al.,


1995).Regarding relevance to this review article is the distribution throughout the rodent CNS of

the receptors for the cytokines IL-1, IL-6, and TNF-α, and these are discussed in more detail

herein below.

6.1.1. IL-1 RECEPTORS IN THE CNS

Early studies investigating the localization of IL-1 receptors in the brain indicated fairly wide-

spread distribution (Turnbull and Rivier, 1999). High levels of specific binding of 125

I-labeled

IL-1β were found in the choroid plexus, dentate gyrus, hippocampus, cerebellum, and olfactory

bulb, with low levels in the hypothalamus of the rat brain slices (Farrar et al., 1987).

Specific binding of 125

I-labeled IL- 1β to membrane preparations of rat hypothalamus and cortex

were also reported (Katsuura et al., 1988). Subsequent studies have confirmed the existence of

IL-1 receptors within the rodent CNS, and IL-1R1 mRNA or IL-1 binding have been demon-

strated on neurons, astrocytes (Ban et al., 1993), cerebrovascular endothelia (Van Der Meer et

al., 1996), neuroblastoma cells (Parnet et al., 1994) and glioblastoma cells, but not on microglia

(Ban et al., 1993). However, the localization within the rat brain appears to differ somewhat

from that which was originally reported, in particular with respect to the presence of IL-1 recep-

tors within the hypothalamus. Furthermore, there are marked differences in the distribution of

IL-1 receptors in rat and mouse brains (Turbull and Rivier, 1999).

Overall, the mouse brain exhibits very low densities of IL-1 receptors as assessed by binding of

125I-labeled IL-1α, IL-1β, or IL-1ra. However, very high levels of labeling are found consistently

in the hippocampus (dentate gyrus, but not CA1 to CA4 pyramidal regions), choroid plexus, and

meninges. Within the dentate gyrus, IL-1 binding appears to be predominantly to neurons. In situ

hybridization histochemical analyses of mouse brains have indicated that IL-1R1 mRNA is ex-

pressed predominantly in the granule cell layer of the dentate gyrus, the entire midline raphe sys-

tem, the choroid plexus, and endothelial cells, but not in the hypothalamus. In contrast, IL-1R2

mRNA has been undetectable in normal mouse brain using in situ hybridization histochemical

procedures (Cunningham et al., 1991).


Analysis using PCR5 and immunocytochemistry techniques demonstrated unequivocally that the

human hypothalamus express both messenger RNA and protein of the IL-1R1 (Hammond. et al.,

1999).

6.1.2. IL-6 RECEPTORS IN THE CNS

Specific IL-6 binding sites binding have been demonstrated in both astrocytoma and

glioblastoma cell lines as well as in extracts of bovine hypothalamus (Cornfield and Sills, 1991).

Messenger RNA encoding α subunit of the IL-6 receptor (IL-6Rα) has been detected in neurons,

microglia, and astrocytes from normal brain tissue, primary cell cultures, or tumor cell lines. Fur-

thermore IL-6Rα mRNA is expressed in several brain regions of the untreated rat and mostly

abundant in the pyramidal cells of the CA1 and CA4 regions of the hippocampus and the granule

cell layer of the dentate gyrus and has also been detected in the hypothalamus, cerebellum, hip-

pocampus, striatum, neocortex, and pons/medulla (Schobitz et al., 1992, Vallieres and Rivest,

1997).

Specific hybridization signals are observed in glial cells of the lateral olfactory tract, in ependy-

mal cells of the olfactory and anterior lateral ventricle and in neurons of the piriform cortex, me-

dial habenular nucleus, neocortex, hippocampus, and hypothalamus. Within the hypothalamus,

IL-6Rα mRNA is present in the ventromedial and dorsomedial regions including the periventric-

ular hypothalamus and in the medial preoptic nucleus. However, the anterior hypothalamus and

PVN display no specific hybridization signal for IL-6Rα mRNA (Schobitz et al., 1992).

The expression of IL-6Rα mRNA in the rat brain appears to be developmentally regulated, with

marked increases in its expression, particularly in the striatum, hypothalamus, hippocampus, and

neocortex, between 2 and 20 days of age. Furthermore, LPS administration markedly elevates

IL-6Rα mRNA levels in several rats within the brain regions (area postrema, bed nucleus of the

5 A technique used to replicate a fragment of DNA and produce a large amount of that sequence


stria terminalis, amygdala, cerebral cortex, claustrum, hippocampus, ME, piriform cortex,

septohippocampal nucleus, PVN, SFO, and OVLT) and over the blood vessels throughout the

brain (Vallieres and Rivest, 1997).

gp130, the signal transducing component of the IL-6 receptor, has also been localized within the

rat brain, expressed in glial, neuronal, Oligodendrocytes, and ependymal cell types (Vallieres and

Rivest, 1997). Furthermore, it has been detected by positive hybridization6 signals in the normal

rat brain and almost detectable in all brain areas includes the hypothalamus and, of particular in-

terest, the PVN (Vallieres and Rivest, 1997).The distribution of immunoreactive gp130 in the rat

brain overlaps that which has been observed for IL-6Rα but is more widespread, consistent with

its role in signal transduction for other members of the IL-6 family (Watanabe et al., 1996).

6.1.3 TNF Receptors in the CNS

In vitro studies have shown that both, TNF-R1 and TNF-R2 mRNA are present in mouse cere-

brovascular endothelium. Furthermore in microglia, astrocytes, and oligodendrocytes, has been

expressed in humans (Wilt et al., 1995), whereas at least one receptor subtype is present in rats

and mice (Dopp et al., 1997). Both undifferentiated and differentiated clonal murine

neuroblastoma cells (N1E cells) express TNF-R1, but not TNF-R2, mRNA (Sipe et al., 1996).

The TNF-R1 immunoreactivity has also been demonstrated in neurons in the substantia nigra of

humans and both TNF-R1 and TNF-R2 immunoreactivities shown in human hippocampal and

striatal neurons. However, there is no evidence that either TNF-a receptor subtype is localized to

hypothalamic regions directly involved in the regulation of HPA axis secretory activity (Turnbull

and Rivier, 1999).

6 In situ hybridization is a technique that uses a labelled complementary RNA strand (i.e. probe)

to localize a specific mRNA sequence in a section of tissue.


6.2. Cytokine expression in the CNS

6.2.1. Basal expression

Many cytokines are synthesized within the brain, although in most cases their expression in

healthy, stress-free subjects is low. Nonetheless, a number of studies have reported the distribu-

tions of IL-1, IL-6, and TNFα immunoreactive or biologically active protein or mRNA in the

brains from normal untreated subjects (Turnbull and Rivier, 1999).

In the human brain, IL-1β immunoreactivity is found within neuronal elements of the hypothal-

amus, including periventricular regions, the PVN, and the median eminence. This distribution is

consistent with a role of IL-1β as a neuroregulator of acute phase responses, and in particular, of

the HPA axis. Although studies in rats also detected neuronal immunoreactive IL-1β in similar

hypothalamic regions, more prominent staining was found in extrahypothalamic sites, particular-

ly the hippocampus (Lechan et al., 1990, Rettori et al., 1994).

In the normal rat or mouse hypothalamus, IL-1β is detectable using sensitive immuno assays

7(Hagan et al., 1993).However, the majority of in situ hybridization studies have found that the

brain parenchyma lacks a readily distinguishable IL-1β mRNA signal (Higgins and Olschowka,

1991, Minami et al., 1991), whereas constitutive expression of IL-1β in the cerebrovasculature of

control animals is readily observable. Similarly, the majority of Northern blot hybridization8 or

RT- PCR studies have found extremely low or undetectable levels of IL-1α or IL-1β mRNA in

the brains of control rats or mice (Gatti and Bartfai, 1993, Higgins and Olschowka, 1991, Laye et

al., 1994), although sufficient sensitivity to demonstrate small diurnal variations in rat brain IL-

1β mRNA expression was achieved in one study (Taishi et al., 1997).

7 A specific type of biochemical tests that measure the presence or concentration of a substance

in solutions that frequently contain a complex mixture of substances.

8 A technique used to study gene expression by detection of RNA (isolated RNA)


Messenger RNA of the gene encoding ICE9 has been demonstrated in murine microglia (Yao and

Johnson, 1997), whole brain homogenates (Keane et al., 1995), homogenates hippocampus

(Laye et al., 1996), and blood vessels (arterioles and venules) throughout the brain parenchyma

of control rats.

Interleukin-1 receptor antagonist mRNA is also present within the rat brain (Gayle et al., 1997,

Ilyin et al., 1996, Licinio et al., 1991), with positive in situ hybridization signal present in the

hypothalamus (particularly the PVN), hippocampus, cerebellum, choroid plexus, and blood ves-

sels throughout the brain (Licinio et al., 1991).

Tumor necrosis factor α immunoreactivity is found in the hypothalamus, caudal raphe nuclei,

and along the ventral surface of the brain in the normal mouse brain (Breder et al., 1993). On the

basis of morphological observations, the majority of staining observed appears neuronal, with

two principal fiber pathways being noted: A periventricular pathway which coursed along the

ventricular system and a pathway associated with the medial forebrain bundle (Breder et al.,

1993). Within the hypothalamus, the PVN represents one of the terminal fields of fibers originat-

ing from the most intensely stained cell groups within the bed nucleus of the stria terminalis. On

the basis of in situ hybridization studies, there is only a weak signal over regions that coincided

with immunoreactive TNF-α (Breder et al., 1993). Finally, IL-6 mRNA has been either undetect-

able (Vallieres and Rivest, 1997 ) or shown to be colocalized with IL6Rα mRNA within several

regions of the normal rat brain, including hypothalamus, cerebellum, hippocampus, striatum,

neocortex, and pons/ medulla ( Schobitz et al., 1993).

6.2.2 Induced Expression

The expression of a number of cytokines within the CNS increases dramatically up on cellular

damage. Accordingly, local concentrations of IL-1β, IL-6, and TNF-α, in particular, are elevated

during CNS bacterial or viral infections, brain trauma, cerebral ischemia, and convulsions. In

addition, their expression is increased during a number of chronic CNS disorders such as multi-

ple sclerosis, Down’s syndrome, and Alzheimer’s disease (Hopkins and Rothwell, 1995). In gen-

eral, when induction of cytokine synthesis within the brain has been demonstrated, microglia ap-

pear to be the major brain cell type that synthesizes ILs, chemokines, TNF and IFN, although

9 An enzyme responsible for cleavage of pro-IL-1β to mature, active IL-1β.


vascular cells, astrocytes, and neurons also contribute to cytokine production (Turnbull and

Rivier, 1999).

The synthesis of cytokines in brain may be induced by stimuli other than those resulting in di-

rect cellular challenge to the CNS, and consequently that cytokines may act as neuroregulators

within the brain in a manner to classical neuropeptides. Indeed, in response to the peripheral ad-

ministration of LPS10

, the CNS expression of a number of cytokines is elevated. In response to

large doses of LPS (0.4–4 mg/kg Ip or IV), the mRNA encoding IL-1α, IL-1β, IL-1rα, IL-6, and

TNF-α are elevated in homogenates of several regions of the mouse brain as assessed by RT-

PCR and Northern blot hybridization methodologies (Gabelle et al., 1995, Gatti and Bartfai,

1993,Muramami et al., 1993). These elevations have been noted within 1h, and peak at approxi-

mate 6 h. However, an important question regarding the induction of cytokines in the brain by

LPS is whether the stimulus causing increased synthesis is of peripheral origin, because large

doses of LPS could, for example, penetrate the BBB in sufficient quantities to stimulate cytokine

synthesis directly. Indeed, LPS is a potent stimulus of IL-1, IL-6, and TNF-α synthesis after its

intracerebroventricular administration (De simoni et al., 1995, Higgins and Olschowka, 1991)

and induces cytokine synthesis by glial cells in cell culture (Sharif et al., 1993). In addition, large

doses of LPS may disrupt the BBB (Boje, 1995, Liu et al., 1996, Lustig et al., 1992, Tunkel et

al., 1991, Shukla et al., 1995), thus permitting the entrance from the periphery of cells (e.g.,

macrophages) that may contribute to the cytokine signal.

Recent studies have suggested that cytokine synthesis in brain may also be induced by stressors

unrelated to infection or inflammation. Hypothalamic expression of IL-1β mRNA (Minami et al.,

1991, Suzuki et al., 1997), IL-1rα mRNA (Suzuki et al., 1997), and IL-1 bioactivity (Shintani et

al., 1995) is increased within 30 min of immobilization stress in the rat, and IL-6mRNA is ele-

vated in the mid brain 4–24 h after restraint stress (Shizuya et al., 1997). Similar paradigms pro-

duce increases in IFN-γ mRNA expression in mouse brain homogenates (Take et al., 1996).

Acute (2 h) or repeated immobilizalation stress in rats increases BDNF mRNA expression in the

10

Lipopolysaccharide is the bacterial cell wall product endotoxin


pPVN and the lateral hypothalamus and decreases BDNF mRNA in the hippocampus, whereas

repeated stress increases NT-3, but not NT-4, mRNA in the hippocampus (Smith et al., 1995).

6.3. Cytokine actions at the level of the CNS

Consistent with the CNS as a primary target of IL-1 action in eliciting pituitary ACTH secretion,

administration either IL-1α or IL-1β directly into the cerebroventricles (intracerebroventricular)

of rats markedly elevates plasma ACTH concentrations. Elevation in plasma ACTH concentra-

tions produced by intracerebroventricular IL-1generally occurs at considerably lower (5- to 20-

fold less) doses than those required by intravenous IL-1 (Katsuura et al., 1988, Rivest et al.,

1992, Vander Meer et al., 1996). Similarly, IL-2, IL-6, TNF-α, and epidermal growth factor

(EGF) have been shown to elevate plasma ACTH and/or corticosterone concentrations when

administered via the intracerebroventricular route. Interleukin-1 infused directly into several

brain sites, including the PVN (Barbanel et al., 1990, Watanobe and Takebe, 1993), median emi-

nence (Matta et al., 1990), and hippocampus (Linthorst et al., 1994), also increases pituitary

ACTH secretion.

The effectiveness of cytokines when administered directly into the brain, and in particular the

fact that lower doses are usually required to stimulate HPA axis secretory activity than when

administered peripherally, have been interpreted as evidence that the activation of the HPA axis

by peripherally administered cytokines occurs via an action within the CNS. This assumption is

based on dose-response studies and with patterns of gene expression of IL-1β and TNFα, within

the PVN (Lee and Rivier, 1994, Rivest et al., 1992, Rivier, 1995).

A number of lines of evidence do suggest that the stimulation of pituitary ACTH and adrenal GC

secretion by either centrally or peripherally administered cytokine is due to an action at or above

the level of the hypothalamus. Indeed, surgical lesioning studies indicate the importance of an

intact hypothalamus to the elaboration of a plasma ACTH response to IL-1β in the rat. Electro-

lytic obliteration of the rat PVN also markedly reduces the rise in plasma ACTH concentrations

produced by a number of cytokines, with inhibition being complete in the cases of

intracerebroventricular IL-1β (Rivest and Rivier, 1991) or intravenous IL-6, approximately70%


after intravenous TNF-α, and 50% when IL-1β is injected intravenously (Kovacs and Elenkov,

1995).

Strong evidence that IL-1 stimulates the secretory activity of the HPA axis primarily by an action

on the CNS comes from studies that have demonstrated that IL-1 rapidly stimulates the secretion

of CRH from the ME into hypophysial portal blood vessels. Corticotropin-releasing hormone is

depleted from the ME of colchicine-treated rats within 1 h of intraperitoneal IL-1β (Berkenbosch

et al., 1987), and CRH concentrations in portal blood are elevated within 30 min of intravenous

IL-1β (Sapolsky et al., 1987). In the perfusates from push-pull cannulas placed within the ME,

CRH concentrations are elevated within 5 min of either intracerebroventricular or intra-PVN

IL-1β (Barbanel et al., 1990) and precede the rise in plasma ACTH after intravenous IL-1β

(Watanobe et al., 1991, Watanobe and Takebe, 1994). Similarly, intravenous TNF-α produces an

immediate rise in CRH secretion (Watanobe and Takebe, 1992). Histological examination of

hypophysiotropic nerve terminals suggests that AVP may (Whitnall et al., 1992) or may not

(Berkenbosch et al.,1989) be cosecreted with CRH in response to peripheral IL-1, whereas elec-

trophysiological data indicate that increased activity in the PVN is selective for neurons contain-

ing CRH only (Saphierd and Ovadia, 1990).

Despite the fact that no IL-1 receptors have been demonstrated in the PVN, a number of studies

demonstrate that IL-1 stimulates the secretion of CRH from the hypothalamus in vitro. Incuba-

tion with subnanomolar doses of IL-1α or IL-1β has consistently been reported to rapidly (within

minutes) increase the release of CRH from rat hypothalamic explants, superfused hypothalamic

tissue, as well as dispersed hypothalamic cell cultures. In addition, IL-1β increases the CRF con-

tent of hypothalamic explants, indicating an increase in CRH peptide production (Hagan et al.,

1993).

Collectively, the rapid effects of IL-1 and other cytokines on hypothalamic CRH secretion in vi-

vo and in vitro, together with the reduction of plasma ACTH responses to cytokines produced by

inhibiting the actions of CRH, provide an extremely strong case for the CNS as a primary site of

cytokine action in the stimulation of HPA axis secretory activity. Nevertheless, a large number of

in vitro studies have also indicated the possibility of direct effects of cytokines on pituitary

ACTH secretion and adrenal GC secretion (Turnbull and Rivier, 1999).


7. Evidence for Direct Effects of Cytokines on Pituitary Adrenocorticotropic

Hormone Secretion

7.1. Cytokine receptors within the pituitary

A number of cytokine receptors have been localized in the pituitary. For example, 125

I-labeled

human IL-1α (Ban et al., 1993, Cunningham et al. 1991, Takao et al., 1992), IL-1β or IL-ra (Ta-

kao et al., 1992), or rat IL-1β (Marquetee et al., 1995) bind specifically to the anterior lobe of the

mouse pituitary gland, with little or no IL-1 binding apparent in the mouse posterior pituitary

(Ban et al., 1993, Marquetee et al., 1995). Pituitary IL-1 binding in the mouse is decreased by

systemic treatment with LPS and increased by immobilization stress, ether-laparotomy stress,

and long-term treatment (7 day) with GC (Ban et al., 1993).

RT-PCR experiments have demonstrated the presence of both IL-1R1 and IL-1R2mRNA in the

whole mouse pituitary (Parnet et al., 1993 ).Insitu hybridization histochemistry experiments

agree with IL-1binding studies and show that IL-1R1 mRNA is present in the mouse anterior, but

not posterior pituitary. Interleukin-1 binding and IL-1R1 and IL-1R2 mRNA have also been

demonstrated in the mouse corticotropic tumor cell line AtT20 (Bristulf and Bartfai, 1995, Ko-

bayashi et al., 1992, Tracey and De souza, 1988).

Interestingly, and in accordance with the stress-induced increases in IL-1 binding in the anterior

pituitary of the mouse, CRF increases IL-1α binding in AtT20 cells, while IL-1β and TNF-α in-

creases the expression of both IL-1R1 and IL-1R2 mRNA (Bristulf and Bartfai, 1995). However,

the expression of IL-1R1 and IL-1R2 by AtT20 cells does not necessarily indicate that normal

corticotropes contain cell-surface IL-1 receptors. Indeed, when IL-1R1 and IL-1R2

immunoreactivities were localized to particular endocrine cell types in the normal mouse anterior

pituitary, no evidence of colocalization of IL-1 receptor with ACTH was apparent (French et al.,

1996). Much less work has focused on the presence of IL-6 and TNF-α receptors within the pi-

tuitary. Rodent anterior pituitaries exhibit binding of 125

I-labeled IL-6 (Ohmichi et al., 1992) and

IL- 6Rα mRNA is expressed in normal rat (Velkeniers et al., 1994) and fetal and adult human

pituitaries (Shimon et al., 1997).


Interleukin-6Rα is also expressed in human ACTH and growth-hormone secreting tumors (Rezai

et al., 1994, Velkeniers et al., 1994). In addition, the IL-6R signaling subunit gp130 is present in

human fetal pituitary cells (Shimon et al., 1997). High concentrations of binding sites form TNF-

α have also been demonstrated in the mouse and rat anterior pituitaries (Wolvers et al., 1993),

AtT20cells and the folliculostelate cell line TtT/GF.

7.2. Cytokine expression in the pituitary

The pituitary has been shown to produce a diverse range of cytokines. Some of these cytokines

(e.g., IL-2, IL-10, LIF, and MIF) have been localized to corticotropes or demonstrated in the

corticotrope cell line AtT20 (Arzt et al., 1992, Bucala, 1994).

In vivo mRNA encoding the cytokines IL-1α, IL-1β, IL-6, LIF, IFN-γ, and TNF-α mRNA in the

pituitary are all elevated by 45 min to 6 h after treatment with LPS (Laye et al., 1994, Muramami

et al, 1993, Tingsborg et al., 1996). Anterior pituitary IL-6 mRNA is also increased by chronic,

local inflammation (Sarlis et al., 1993). The constitutive expression of IL-1ra in the pituitary

(Gabellec et al., 1995, Gatti and Bartfai, 1993, Licinio et al., 1991) is of particular interest given

its ability to antagonize the effects of IL-1 agonists, suggesting that the responsiveness of the pi-

tuitary to IL-1 may be modulated at a local level. Interleukin-1ra mRNA has been reported to be

either unaffected (Gatti and Bartfai, 1993) or induced (Gabellec et al., 1995, Licinio et al., 1991)

by systemic treatment with LPS.

The regulation of IL-6 secretion from anterior pituitary cell cultures has been investigated exten-

sively. Anterior pituitary cells constitutively produce IL-6 and the secretion of this cytokine can

be induced within 6hours treatment with LPS, IL-1a, IL-1b, TNF-α, the IFN family,

phorbolmyrisate and agents that elevate cAMP (Spangelo et al., 1991).

Accordingly, dibutyryl cAMP, prostaglandin E2, forskolin, and cholera toxin all increase IL-6

secretion from rat anterior pituitary cell cultures (Spangelo et al., 1991, Carmeliet et al., 1991).

Some (VIP, pituitary adenylate cyclase activating peptide (PACAP), and calcitonin gene-related

peptide) but not all (CRF, growth hormone releasing factor) neuropeptides that utilize cAMP-

coupled receptors for signaling, therefore, also stimulate IL-6 secretion in anterior pituitary cells.

However, the induction of IL-6 secretion from anterior pituitary cells by IL-1b does not appear to


be mediated by cAMP-dependent pathways, since in these cells, no increase in intracellular

cAMP is apparent after treatment with IL-1β (Spangelo and Gorospe, 1995).

Glucocorticoids inhibit basal and IL-1β stistimulated (Carmeliet et al., 1991, Spangelo et al.,

1991) IL-6 release from rat anterior pituitaries. In addition to secretion from anterior pituitary

cells, IL-6 is released by neurointermediate lobe cells in culture, with IL-1β and LPS again being

potent secretagogues. The cell source within the normal anterior pituitary does not appear to be a

classical endocrine cell type. Rather, folliculo stellate11

(FS) cells are the major sources of IL-6

FS-like cell line has been isolated (TtT/GF) and constitutively secrete IL-6, and IL-6 secretion is

enhanced by TNF-α, VIP, PACAP) and IL-1β (Kobayashi et al., 1992).

7.3. Direct effects of cytokines on pituitary ACTH

In vitro studies indicating that with the exception of activin, which inhibits POMC mRNA ex-

pression and ACTH secretion in the corticotropic tumor cell line AtT20 and reduces ACTH se-

cretion from primary cultures of rat anterior pituitary cells all other cytokines studied have been

reported to either enhance or have no effect on either ACTH secretion or POMC mRNA expres-

sion in otherwise untreated pituitary cells (Bilezikjian et al., 1991).

IL-1β, IFN-γ, and GM CSF stimulate ACTH secretion from cultured human pituitary adenoma

cells from patients with Cushing’s disease (Malarkey and Zvara, 1989). The duration of exposure

of AtT20 cells and human pituitary adenoma cells to cytokines required to elicit statistically sig-

nificant increases in ACTH secretion has, in general, been long. Although one report indicates

increases in ACTH produced by either IL-1 or IL-6 within 2h (Woloski et al.,1985), the majority

have used incubation times ranging from 6 to 72 h (Akita et al.,1995 ,Brown et al., 1987 , Ray et

al., 1996, Stefana et al., 1996 ). The fact that many cytokines have a stimulatory effect on pitui-

tary tumor cells indicates the ability of signal transduction path ways activated by cytokine-

cytokine receptor interaction to influence POMC expression and/or ACTH secretion. However, it

is unclear to what extent corticotrope tumors accurately represent normal anterior pituitary

corticotropes.

11

Folliculostelate cells are of monocytic lineage and are thought to be involved in paracrine regula

tion of hormone secretion from the pituitary


For example, although AtT20 cells possess both IL-1R1 and IL-1R2 mRNA (Bristulf and

Bartfai, 1995, De souza et al., 1989, Tracey and De Souza, 1988), immuno staining of normal

mouse pituitary does not show significant IL-1 receptor expression by corticotropes (French et

al., 1996).

8. Evidence for Direct Actions of Cytokines on Adrenal Glucocorticoids Secre-

tion

The adrenal gland displays no positive in situ hybridization signal for IL-1R1 mRNA, whereas

IL-6Rα mRNA has been detected mainly in the zona glomerulosa and fasciculata in human ad-

renals (Path and Bornstein, 1997) and also in the adrenal medulla (Gadient et al., 1995).

8.1. Cytokine expression in the adrenal gland

In the adrenal gland, large constitutive pools of IL- 1α and IL-1β have been identified. Interleu-

kin-1α, IL-1β, and IL-1ra immunoreactivities have been demonstrated in adrenal chromaffin

cells (Bartfai et al., 1990). In addition, IL-1α, IL-1β, ICE, and IL-1ra mRNA are present in the

adrenal cortex and are markedly elevated in both adrenal medulla and cortex 90 min after intra-

venous or intraperitoneal LPS (Schultzberg et al., 1995, Tingsborg et al., 1997).

Interestingly, the IL-1-related cytokine IL-18/IL-1γ is also synthesized within the rat adrenal cor-

tex, mainly in the zona reticularis and fasciculata, and is strongly induced by acute cold stress

(Conti et al., 1997). Interleukin-6 mRNA is also present throughout the human adrenal cortex

(Gonzalez et al., 1994, Path and Bornstein, 1997), and rat adrenal gland extracts contain IL-6

mRNA (Gadient et al., 1995, Muramami et al., 1993, Schobitz et al., 1993), which is markedly

induced 2hours after intraperitoneal LPS (Muramami et al., 1993). Although TNF-α mRNA has

been described throughout the cortex of human adult adrenals, particularly in steroid-producing

cells, TNF-α immunoreactive protein has been detected in only 12 of 22 fetal, and in 0 of 7 adult,

human adrenals (Jaattela et al., 1990).

A number of growth factors are also present in the adrenal: basic fibroblast growth factor mRNA

or protein is present in whole human adrenals, in rat, bovine cortex or medulla, TGF-β1 mRNA


and protein in bovine adrenal cortex and mouse whole adrenal and NT-3 protein has been report-

ed in whole rat adrenal (Basile and Holzwarth., 1993, Grothe and Unsicker, 1990).

Studies of primary cultures of dispersed adult rat adrenal glands have indicated the likely cellular

sources and major secretagogues of the cytokines IL-6 and TNF-α within the adrenal gland. Alt-

hough the zona fasciculata/reticularis produce small amounts of TNF-α and IL-6, the primary

source of IL-6 in the rat adrenal is the zona glomerulosa. The secretion of TNF-α and IL-6 from

adrenal glomerulosa cells is stimulated in a dose-dependent manner by LPS, IL-1α, and IL-1β.

Furthermore, IL-6 secretion from these cells is enhanced by protein kinase C activators, the cal-

cium ionophore ionomycin, prostaglandin E2, forskolin, and angiotensin II (Judd and Macleod,

1995). Unlike most cell types that produce IL-6, dexamethasone does not influence either basal

or IL-1b-stimulated IL-6 secretion in zona glomerulosa cells (Judd and Macleod, 1992). Interest-

ingly, ACTH increases the release of IL-6 from zona glomerulosa cells but not zona

fasciculata/reticularis, despite similar ACTH-stimulated cAMP levels in each cell type (Judd and

Macleod, 1992). Such ACTH-induced IL-6 release from the adrenal suggests that activation of

the HPA axis per se may cause IL-6 secretion from the adrenal. Like IL-6, TNF-α secretion is

stimulated by protein kinase C activators and ionomycin. However, in stark contrast to IL-6, ba-

sal and stimulated TNF-α release is dose dependently inhibited by ACTH and dibutyryl cAMP

(Judd and Macleod, 1995). Similarly, differentia effects on IL-6 and TNF-α secretion from zona

glomerulosa cells are observed with serotonin and adenosine (Ritchie et al., 1996).

8.2. Direct effects of cytokines on adrenal glucocorticoids secretion

Despite a lack of evidence for the presence of IL-1, IL-6, or TNF-α receptors within the adrenal

gland, direct actions of these cytokines on GC secretion have been demonstrated. In vivo, pe-

ripheral administration of IL-1β has been reported to either stimulate or exert no effect on

corticosterone secretion in hypophysectomized rats and to induce secretion of GC in anesthetized

rats with isolated adrenal glands (Roh et al., 1987). The doses required to observe direct effects

of IL-1β on adrenal corticosterone secretion in vivo have, however, been extremely high, which

is 35 μg /rat and casts doubt on the physiological relevance of this effect (Gwosdow et al., 1990).


In vitro studies have indicated that IL-1β does not influence either basal or ACTH-stimulated GC

production from human fetal adrenal tissue either in cell or organ culture (Harlin and Parker,

1991). However, either IL-1α or IL-1β increases GC secretion from rat quartered adrenals, rat

adrenal slices, or rat, bovine and human dispersed adrenal cells (Mazzocchi et al., 1993,

O’Connell et al., 1994, Tominaga et al., 1991, Winter et al., 1990). Similarly, IL-2, IL-3, and IL-

6 induce GC secretion from various adrenal cell preparations (Darling et al., 1989, Tominaga et

al., 1991), and IL-6 potentiates corticosterone secretion induced by low concentrations of ACTH

(Salas et al., 1990).

Tumor necrosis factor-α stimulates cortisol secretion from adult adrenocortical cells (Darling et

al., 1989) but inhibits ACTH-induced cortisol secretion from human fetal adrenal tissue and cul-

tured cells (Jaattela et al., 1991). Interferon-γ stimulates corticosterone secretion from primary

dispersed rat adrenal cells (Gisslinger et al., 1993) and normal human adrenal slices (Cardoso et

al., 1990), whereas NGF does not influence either basal or ACTH-stimulated corticosterone pro-

duction from dispersed rat adrenal cell cultures (Scaccianoce et al., 1993).

Finally, these in vitro studies provide strong evidence that some cytokines may influence GC se-

cretion directly. However those studies required incubations in excess of 12h to observe signifi-

cant effects of cytokines on GC secretion.

9. Mechanisms OF Hypothalamic Pituitary Adrenal Axis Activation by Inter-

leukin-1

The distributions of various cytokines and their receptors throughout the brain, pituitary, and to a

lesser extent in the adrenal provide an anatomic basis for the hypothesis that cytokines influence

the function of these organs.

Elucidating the mechanisms by which particular cytokines may activate the HPA axis during a

particular threat to homeostasis has focused on the cytokine IL-1 and to a much lesser extent IL-

6 and TNFα.


Almost all proinflammatory cytokines stimulate the HPA axis in vivo (Turnbull and Rivier,

1999) and proopiomelanocortin (POMC) expression in vitro (Katahira et al., 1998). HPA stimu-

lation occurs either at the hypothalamic level (IL-1β, TNFα), inducing CRH gene expression and

CRH release. In addition to CRH, inflammatory cytokines also trigger central ACTH

secretagogues such as noradrenaline (Giovambattista et al., 2000), pituitary adenylate cyclase-

activating polypeptide (PACAP), vasopressin, and other cytokines. Furthermore stimulation of

HPA axis also occurs at the level of pituitary corticotrophs. IL-2, interferons, and the gp130 cy-

tokine family participate in ACTH regulation and mediate the immuno neuroendocrine interface


9.1. Direct Actions of IL-1 on Pituitary and Adrenal

IL-1 may be capable of having direct actions on the pituitary to enhance the secretion of ACTH

and on the adrenal cortex to increase GC secretion. Receptors for IL-1 are clearly present in the

anterior pituitary, although it is unlikely that these are expressed on normal corticotropes. The

pituitary and adrenals clearly would be exposed to IL-1 if its concentrations in blood were ele-

vated (e.g., severe endotoxemia). In addition, IL-1 can be synthesized locally within these tis-

sues. However, it seems clear that prolonged exposure of the pituitary or adrenals to IL-1 is nec-

essary to elicit the release of ACTH or GC, respectively. Therefore, direct actions of IL-1 on ei-

ther the pituitary or adrenal do not appear to account for a significant component of the hormone

secretion observed in response to acute exposure to IL-1 in vivo.

Circumstances involving prolonged increases in cytokines, for example, during chronic inflam-

mation (Sarlis et al., 1993,), may well involve direct actions of IL-1 or other cytokines on the

pituitary ACTH and/or adrenal GC secretion. Furthermore, enhanced pituitary or adrenal synthe-

sis of IL-1 may regulate these glands’ growth and development (Arzt and Stalla et al., 1996,

Renner et al., 1995, Zieleniewski and Stepien, 1995). Similarly, a number of other interleukins

(e.g., IL-2, IL-6) and growth factors (e.g., EGF) have been shown to influence the growth of the

pituitary or adrenal glands (Arzt and Stalla et al., 1996, Pereda et al., 1996).

A large body of evidence indicates that the level of the HPA axis primarily affected by IL-1 is

the hypothalamus. This is true whether IL-1 has been administered directly into the brain or into


the periphery. This raises the question of how a blood-borne, large, hydrophilic peptide such as

IL-1 accesses the CNS to influence hypothalamic secretions.

To address for the above raised question different possible mechanisms have been proposed.

These mechanisms includes blood-borne cytokine acting at a Circumventricular organ (CVO), at

vagal or other afferent nerves, altering the permeability of the BBB to other substances, disrupt-

ing the BBB, enhancing or inducing the passage of immune cells from blood to brain, and affect-

ing the release of another substance which in turn crosses the BBB or acts through one of these

mechanisms. Herein, Attempts has been made to clarify only some of the proposed mechanisms

related to the topic of this paper.

9.2. Penetration of Cytokines into Brain

The transport of solutes out of vascular compartments and into perivascular tissue (or vice versa)

occurs via either paracellular or transcellular mechanisms. Within the cerebrovaculature, the

paracellular route is particularly impermeable due to the presence of the BBB12

. The paracellular

Ultrafiltration of solutes into and out of tissues that occurs in peripheral vascular beds does there-

fore not occur in most cerebrovascular beds, at least while the BBB remains intact. Furthermore,

the large molecular size (8– 65 kDa) and hydrophilic nature of cytokines preclude their move-

ment transcellularly by simple diffusion to any appreciable extent. Indeed, early studies conclud-

ed that the BBB was impermeable to IL-1 (Blatteis, 1990, Coceani et al., 1988). However,

transport of cytokines via the paracellular route can occur (Banks et al., 1994), when BBB integ-

rity is compromised, and saturable transcellular transport mechanisms for a number of cytokines

have now been described.

12

BBB consists primarily of nonfenestrated endothelial cells that are connected by tight junc-

tions and thus form a continuous cell layer that has the permeability properties of a continuous

plasma membrane.


FIG.4 Proposed Models by Which Lnterleukin-1 Influences Secretory Activity of Hypothalamic

Pituitary-Adrenal Axis (Source: Turnball and Rivier, 1999)

9.3. Cytokines and Blood-Brain Barrier Integrity

Loss of BBB integrity may occur during inflammatory insults to the brain such as those accom-

panying CNS disease (e.g., multiple sclerosis, meningitis, brain tumors, and AIDS dementia),

brain trauma, cerebrovascular lesions, or seizures (Johansson, 1995). Furthermore, administra


tion of large doses of LPS increases BBB permeability (Boje, 1995, De Vries et al., 1996, Liu et

al., 1996, Lustig et al., 1992, Tunkel et al., 1991). Such disruption of the BBB enables not only

the passage of large peptides such as cytokines, but also augments the rate of entry of cells, such

as macrophages, monocytes, lymphocytes, and neutrophils, which are capable of cytokine syn-

thesis and secretion, but whose passage into the normal healthy brain is very limited.

The association between peripheral inflammatory events and the CNS production of cytokines

has led to a number of studies investigating the possible influence of cytokines on BBB permea-

bility. In monolayer cultures of cerebral endothelial cells, LPS or IL-1β, IL-6 or TNFα produces

a decline in transendothelial electrical resistance data supportive of an elevation in BBB permea-

bility (DeVries et al., 1996). In vivo studies have demonstrated that intracerebroventricular TNF-

increases BBB permeability in the rat (Kim et al., 1992) and pig (Megyeri et al., 1992), and en-

hanced brain TNF-α producation has been linked to the increased BBB permeability associated

with a number of CNS inflammatory conditions (Sharief et al., 1992, Shohami et al., 1996).

Enhanced BBB permeability as a result of either CNS or severe peripheral infection may there-

fore permit the entry of cytokines themselves or cytokine-producing cells into the CNS, and cy-

tokines so derived may contribute to CNS-mediated acute phase responses. However, it is clear

that the initial neuroendocrine effects of peripheral administered cytokines or LPS can be ob-

served more quickly, and at lower doses, than can be accounted for by damage to the BBB


9.4. Carrier-mediated transport of cytokines across the blood-brain barrier

Transcellular, saturable transport mechanisms afford a means of cytokine entry into the brain,

even when BBB integrity is not compromised (Banks et al., 1995). These include saturable

transport mechanisms for IL-1 α, IL-1β, IL-6, IL-1ra and TNF-α but not IL-2 (Gutierrez et al.,

1994).

The members of the IL-1 family, IL-1α, IL-β and IL-1ra share the same transporters (Gutierrez et

al., 1994), but IL-6 entry into brain is not inhibited by the presence of unlabeled IL-1α or TNF-α

(Banks et al., 1994), whereas competition studies with IL-1α, IL-1β, IL-6, and MIP-1a have

demonstrated selectivity of the TNF- α transporter (Gutierrez et al., 1994).

9.5. Role of Readily Diffusible Intermediates


The apparent lack of IL-1 receptors within neuronal elements in the PVN and the limited entry of

IL-1 into the CNS have led to the hypothesis that IL-1 stimulates the HPA axis via enhancing the

production of intermediates that directly interact with hypothalamic neurosecretory processes.

These intermediates include classical neurotransmitters, such as catecholamines, serotonin

(Gemma et al., 1991, Linthorst et al., 1994), histamine (Givalois et al., 1996, Knigge et al.,

1994), and more readily diffusible agents such as the lipid autacoids, eicosanoids, and the gase-

ous mediator nitric oxide (NO).

9.6. Cytokines Actions at Circumventricular Organs

Besides to cytokine entry into the CNS by way of carrier mediated transport or diffusion through

a disrupted BBB, a number of regions of CNS relatively devoid of a BBB permit cytokine inter-

action with neuronal elements. These CVO include structures lining the anteroventral border of

the third ventricle (AV3V) (namely, the OVLT and SFO), the ME, and the AP, posterior lobe of

the pituitary, subcommisural organ, and the pineal gland. Their capillaries do not form tight junc-

tions and are thus far more readily penetrable via the paracellular route (Gross and Weindl,

1987).

Circumventricular organs not only contain capillaries with far greater permeability than the rest

of the CNS, but the capillary density in these regions is extraordinarily high. Penetration of cyto-

kines into brain parenchyma within the CVO does not imply that they may diffuse to interact

with deeper brain structures, however, because tight junctions between modified ependymal cells

in these regions form a diffusion barrier between CVO and the rest of the brain. But these leaky

sites do provide a means with which cytokines such as IL-1 can influence neuronal activity in

these regions of the CNS (Johnson and Gross, 1993).


10. Conclusions and Recommendations

Cytokines are capable of influencing HPA axis secretory activity, with most having stimulatory

action. Cytokine receptors have been cloned, characterized and localized to many neuro endo-

crine tissues (hypothalamus, pituitary).

Central nervous system, pituitary and adrenal are capable of synthesizing a variety of cytokines,

whose levels are increased during endotoxemia. Recent studies suggesting that cytokine regula-

tion of the HPA axis may occur not only during infection, inflammation and trauma, but also

during psychological and physical stress.

Even though, the pituitary and adrenal glands represent potential targets of cytokine action on the

HPA axis during prolonged exposure, the majority of evidence indicates that either direct or indi-

rect stimulation of hypothalamic CRF secretion is the primary means by which the cytokines ac-

tivates the HPA axis.

The neuroanatomy and neuropharmacology pathways by which cytokines have been proposed to

influence the neuroendocrine hypothalamus are numerous and diverse. For example accurate

models of the mechanisms by which IL-1 activates the HPA axis have to take into account the

consistently reported inhibitory effects of either inhibitors of PG synthe sis or disruption of

catecholaminergic input into the hypothalamus.

Recommendations

1. Even though, numerous studies investigating the mechanisms of IL-1 induced activation

of the HPA axis, further studies on mechanisms of by which multiple cytokines (e.g., IL1

and IL-6) and another proinflammatory cytokines on HPA axis activation may strengthen

the evidence that how proinflammatory cytokines influence the HPA axis and vice versa.

2. The proposed mechanisms of activation of the HPA axis by cytokines have not explain

more on the effect of a single cytokine in response to a homeostatic threat. So that more

explanation requires to magnify the effect of single cytokine on the effect of the HPA ax-

is.


References

Adashi, The potential role of IL-1 in the ovulatory process: an evolving hypothesis. Journal of

Reproductive Immunology 35: 1–9, 1997.

Akita, Webster, Ren, Takino, Said, Zand and Melmed. Human and murine pituitary expression

of leukemia inhibitory factor. Novel intrapituitary regulation of Adrenocorticotropin

hormone synthesis and secretion. Journal of Clinical Investigation 95: 1288–1298,

1995.

Anastasia Kariagina, Dmity Romanenko, Song-Guangren and Vera Chesnokova. Hypothalamic-

Pituitary Cytokine Network. Endocrinology January 2004, 145(1):104–112.

Arzt and Stalla. Cytokines: autocrine and paracrine roles in the anterior pituitary.

Neuroimmunomodulation 3: 28– 34, 1996.

Arzt, Steizer, Renner, Lange, Muller and Stalla. Interleukin-2 and interleukin-2 receptor expres-

sion in human corticotropic adenoma and murine pituitary cell cultures. Journal Clinical

Investigation 90: 1944–1951, 1992.

Atkins, Gould, Allegretta, Dempsey, Rudders, Parkinson, Reichlin and Mier. Phase I evaluation

of recombinant interleukin-2 in patients with advanced malignant disease. Journal Clin-

ical Oncology 4: 1380–1391, 1986.

Ban, Marquette, Sarrieau, Fitzpatrick, Fillion, Milon, Rostene and Haour. Regulation of interleu-

kin-1 receptor expression in mouse brain and pituitary by lipopolysaccharide and gluco-

corticoids. Neuro endocrinology inter58: 581–587, 1993.

Banks, Kastin and Broadwell. Passage of cytokines across the blood-brain barrier.

Neuroimmunomodulation 2: 241–248, 1995.

Banks, Kastin and Gutierrez. Penetration of interleukin-6 across the murine blood-brain-barrier.

Neuroscience Letter179: 53–56, 1994.

Barbanel, Ixart, Szafarczyk, Malaval and Assenmacher. Intra hypothalamic infusion of interleu-

kin-1 β increases the release of corticotropin-releasing hormone (CRH 41) and adreno-

corticotropic hormone (ACTH) in free-moving rats bearing a push-pull cannula in the

median eminence. Brain Research 516: 31–36, 1990.

Bartfai, Andersson, Bristulf, Schultzberg and Svenson. Interleukin-1 in the noradrenergic

chromaffin cells in the rat adrenal medulla. Ann. NY Acad. Sci. 207–213, 1990.


Basile and Holzwarth. Basic fibroblast growth factor may mediate proliferation in the compensa-

tory adrenal growth response. American Journal of Physiology 265 (Regulatory Integra-

tive Comparative Physiology 34): R1253–R1261, 1993.

Berkenbosch, Van oers, Del rey, Tilders and Besedovsky. Corticotropin-releasing factor-

producing neurons in the rat activated by interleukin-1. Science 238: 524–526, 1987.

Besedovsky, Sorkin, Keller and Muller. Changes in blood hormone levels during the immune

response. Proc. Soc. Exp. Biol. Med. 150: 466–470, 1975.

Besedovsky, Del rey, Sorkin and Dinarello. Immuno regulatory feedback between interleukin-1

and gluco corticoid hormones. Science 233: 652–654, 1986

Bilezikjian, Blount, Campen, Gonza Lez-Manchon and Vale. Activin-A inhibits

proopiomelanocortin messenger RNA accumulation and Adrenocorticotropin secretion

of AtT20 cells. Molecular Endocrinology 5: 1389–1395, 1991.

Blatteis. Neuromodulative actions of cytokines. Yale J. Biol. Med. 63: 133–146, 1990.

Boje. Cerebrovascular permeability changes during experimental meningitis in the rat. Journal of

Pharmacology Experiment Ther. 274: 1199–1203, 1995.

Breder, Tsujimoto, Terano, Scott and Saper. Distribution and Characterization of Tumor Necro-

sis Factor-a-Like Immunoreactivity in the Murine Central Nervous System. The Journal

of Comparative Neurology 337:543-567, 1993.

Bristulf and Bartfai. Interleukin-1β and tumor necrosis factor-α stimulate the mRNA expression

of interleukin-1 receptors in mouse anterior pituitary AtT-20 cells. Neurosci. Lett. 187:

53– 56, 1995.

Brown, Smith and Blalock. Interleukin-1 and interleukin-2 enhance proopiomelanocortin gene

expression in pituitary cells. Journal of Immunology 139: 3181–3183, 1987.

Bucala. A previously unrecognized pituitary hormone and macrophage cytokine is a pivotal me-

diator in endotoxic shock. Circ. Shock 44: 35–39, 1994.

Burger and Dayer. Inhibitory cytokines and cytokine inhibitors. Neurology.1995 Jun; 45(6 Suppl

6):S39-43

Buttini and Boddeke. Peripheral lipopolysaccharide stimulation induces interleukin-1β messen-

ger RNA in rat brain micro glial cells. Neuroscience 65: 523–530, 1995.

Cannon and Dinarello. Increased plasma interleukin-1 activity in women after ovulation. Sci-

ence 227: 1247–1249, 1985.


Cardoso, Arzt, Coumroglon and Andrada. Alpha-interferon induces cortisol release by human

adrenals in vitro. Int. Arch. Allergy Appl. Immunol. 93:263–266, 1990.

Carmeliet, Vankelecom, Van damme, Billiau and Denef. Release of interleukin-6 from anterior

pituitary cell aggregates: developmental pattern and modulation by glucocorticoids and

forskolin. Neuroendocrinology 53: 29–34, 1991.

Coceani, Lees and Dinarello. Occurrence of interleukin-1 in cerebrospinal fluid in the conscious

cat. Brain Res. 446: 245–250, 1988.

Cohen MC and Cohen S. Cytokine function: a study in biologic diversity. American Journal of

Clinical Pathology.105:589-98, 1996.

Colotta, Muzio, Bertini, Polentarutti, Sironi, Giri, Dower, Sims and MantoVani.Interleukin-1

type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 261: 472–475,

1993.

Conti, Jahng, Tinti, Son and Joh. Induction of interferon- γ inducing factor in the adrenal cortex.

Journal of Biol. Chem. 272: 2035–2037, 1997.

Cornfield and Sills. High affinity interleukin-6 binding sites in bovine hypothalamus. Eur. J.

Pharmacol. 202: 113–115, 1991.

Crown, Jakubowski, Kemeny, Gordon, Gasparetto, Wong, Sheridan, Toner and Botet. A phase I

trial of recombinant human interleukin-1 β alone and in combination with

myelosuppressive doses of 5-fluolrouracil in patients with gastrointestinal cancer. Blood

78: 1420–1427, 1991.

Cunningham, Wada, Carter, Tracey, Battey and De souza. Localization of interleukin-1 receptor

messenger RNA in murine hippocampus. Endocrinology 128: 2666–2668, 1991.

Curti, Urba, Longo, Janik, Sharfman, Miller, Cizza, Shimizu, Oppenheim, Alvord and Smith.

Endocrine effects of IL-1 alpha and beta administered in a phase I trial to patients with

advanced cancer. J. Immunother. Emphasis Tumor Immunol.19: 142–148, 1996.

Daban, Vieta, Mackin, Young. Hypothalamic-pituitary-adrenal Axis and Bipolar Disorder, Psy-

chiatry Clinical North America 28: 469–480, 2005.

Darling, Goldstein, Stull, Gorthsch Both and Norton. Tumor necrosis factor: immune endocrine

interaction. Surgery 106: 1155–1160, 1989.


De simoni, Del Bo, Deluigi, Simard and Forloni. Central endotoxin induces different patterns of

interleukin (IL)-1b and IL-6 messenger ribonucleic acid expression and IL-6 secretion in

the brain and periphery. Endocrinology 136: 897–902, 1995.

De vries, Blom-Poosemalen, Deboer, Van berkel, Breimer and Kuiper. Effect of endotoxin on

permeability of bovine cerebral endothelial cell layers in vitro. J. Pharmacol. Exp. Ther.

277: 1418–1423, 1996.

Denicoff, Durkin, Lotze, Quinlan, Davis, Listwak, Rosenberg, and Rubinow. The neuroendo-

crine effects of interleukin-2 treatment. J journal of Clinical Endocrinology Metabolism

69: 402–410, 1989.

Dinarello Charles A. Interleukin-1 and Interleukin-1Antagonism. Blood 1991, 77(8): 1627-52.

Dinarello Charles A. Biological basis for interleukin-1 in disease. Blood 1996, 87: 2095-147

Farrar, Kilian, Ruff, Hill and Pert. Visualization and characterization of interleukin 1 receptors in

brain. Journal of Immunology 139: 459–463, 1987.

French, Zachary, Dantzer, Frawley, Chizzonite, Parnet and Kelley. Dual expression of p80 type I

and p68 type II interleukin-1 receptors on anterior pituitary cells synthesizing growth

hormone. Endocrinology 137: 4027–4036, 1996.

Fukata, Usui, Naitoh, Nakai and Imura. Effects of recombinant interleukin-1a, -1b, 2 and 6 on

ACTH synthesis and release in mouse pituitary tumor cell line AtT20. J. Endocrinol.

122: 33–39, 1989.

Gabellec, Griffais, Fillion and Haour. Expression of interleukin 1a, interleukin 1b and interleukin

1 receptor antagonist mRNA in mouse brain: regulation by bacterial lipopolysaccharide

(LPS) treatment. Brain Res. Mol. Brain Res.31: 122–130, 1995.

Gadient, Lachmund, Unsicker and Otten. Expression of interleukin-6 (IL-6) and IL-6 receptor

mRNAs in rat adrenal medulla. Neuroscience Letters 194: 17–20, 1995.

Gatti and Bartfai. Induction of tumor necrosis factor alpha mRNA in the brain after peripheral

endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Res.

624: 291–294, 1993.

Gayle, Ilyin and Plata-Salaman. Interleukin-1 receptor type I mRNA levels in brain regions from

male and female rats. Brain Res. Bull. 42: 463–467, 1997.

Gemma, Ghezzi and DeSimoni. Activation of the hypothalamic serotoninergic system by inter-

leukin-1. Eur. J.Pharmacol. 209: 139–140, 1991.


Gisslinger, Svoboda, Clodi, Gilly, Ludwig, Havelec and Luger. Interferon-alpha stimulates the

hypothalamo-pituitary axis in vivo and in vitro. Neuro endocrinology 57: 489–495,

1993.

Givalois, Siaud, Mekaouche, Ixart, Malaval, I.assenmacher, and Barbanel. Involvement of cen-

tral histamine in the early phase of ACTH and corticosterone responses to endotoxin in

rats. Neuroendocrinology 63: 219–226, 1996.-

Gonzalez-Hernandez, Ehrhart-Bornstein, Senspath-Schwalbe, Scherbaum and Bornstein. Human

adrenal cells express tumor necrosis factor-alpha messenger ribonucleic acid: evidence

for paracrine control of adrenal function. Journal of Clinical Endocrinology Metabolism

81: 807–813, 1996.

Greenfeder, Nunes, Kwee, Labow, Chizzonite and Ju. Molecular cloning and characterization of

a second subunit of the interleukin 1 receptor complex. J. Biol Chem. 270: 13757–

13765, 1995.

Gross and Weindl. Peering through the windows of the brain. Journal Cerebral Blood Flow Me-

tabolism 7: 663–672, 1987.

Grothe and Unsicker. Immuno cytochemical mapping of basic fibroblast growth factor in the de-

veloping and adult rat adrenal gland. Histochemistry 94: 141–147, 1990.

Gutierrez, Banks and Kastin. Blood-borne interleukin-1 receptor antagonist crosses the blood-

brain barrier. J. Neuroimmunol. 55: 153–160, 1994.

Gwosdow, Kumar and Bode. Interleukin-1 stimulation of the hypothalamo-pituitary-adrenal axis.

American Journal Physiology 258 (Endocrinology Metabolism 21): 65–70, 1990.

Hagan, Poole and Bristow. Endotoxin stimulated production of rat hypothalamic interleukin-1β

in vivo and in vitro, measured by specific immuno radiometric assay. Journal Molecular

Endocrinology 11: 31–36, 1993.

Hammond, Smart, Toulmond, Suman-Chauhan, Hughes and Hall, the interleukin-1 receptor is

expresses in human hypothalamus. Brain.122:1697-1707, 1999

Hannum, Wilcox, Joslin, Dripps, Heimdal, Armes, Sommer, Eisenspath Berg and Thompson.

Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343:

336–340, 1990.

Harlin CA and Parker CR Jr. Investigation of the effect of interleukin-1 beta on steroidogenesis

in the human fetal adrenal gland. Steroids 56: 72–76, 1991.


Higgins and Olschowka. Induction of interleukin-1βmRNA in adult rat brain. Brain Research,

Molecular Brain Research 9: 143– 148, 1991.

Hopkins and Rothwell. Cytokines and the nervous system I: expression and regulation. Trends

Neuroscience 18: 83–88, 1995.

Ilyin and Plata-Salaman. In vivo regulation of the IL-1b system (ligand, receptors I and II, recep-

tor accessory protein and receptor antagonist) and TNF-α mRNAs in specific brain re-

gions. Biochem. Biophys. Res. Commun. 227: 861–867, 1996.

Jaattela, Carpen, Stenman and Saksela. Regulation of ACTH-induced steroidogenesis in human

fetal adrenal glands by rTNF-alpha. Molecular Cell Endocrinology 68: R31–R36, 1990.

Johansson. The blood-brain barrier and perivascular cells. In Immune Responses in the Nervous

System: Bios Scientific.1–26, 1995

Johnson and Gross. Sensory Circumventricular organs and brain homeostatic pathways. FASEB

J. 7: 678–686, 1993.

Judd and Macleod. Adrenocorticotropin increases interleukin-6 release from rat adrenal zona

glomerulosa cells. Endocrinology 130: 1245–1254, 1992.

Katoh-semba, Kaisho, Shintani, Nagahama and Kato. Tissue distribution and immuno

cytochemical localization of neurotrophin-3 in the brain and peripheral tissues of rats. J.

Neurochemical. 66: 330–337, 1996.

Katsuura, Gottschall and Arimura. Identification of a high affinity receptor for interleukin-1 beta

in rat brain. Biochem. Biophys. Res. Commun. 156: 61–67, 1988.

Keane, Giegel, Lipinski, Callahan and Shivers. Cloning, tissue expression and regulation of rat

Interleukin 1β converting enzyme. Cytokine 7: 105–110, 1995.

Keramidas, Bourgariat, Tabone, Corticelli, Chambazandfeige. Immunolocalization of transform-

ing growth factor-beta 1 in the bovine adrenal cortex using antipeptide antibodies. En-

docrinology 129: 517–526, 1991.

Kim, Wass, Cross and OpaL. Modulation of blood-brain-barrier permeability by tumor necrosis

factor an antibody to tumor necrosis factor in the rat. Lymphokine Cytokine Res. 11:

293–298, 1992.

Kishimoto, Akira, Narazaki and Taga. Interleukin-6 family of cytokines and gp130. Blood 86:

1243–1254, 1995.


Knigge, Kjaer, Jorgensen, Garbarg, Ross, Rouleau and Warberg. Role of hypothalamic

histaminergic neurons in mediation of ACTH and beta-endorphin responses to LPS en-

dotoxin in vivo. Neuroendocrinology 60: 243–251, 1994.11-

Kobayashi, Fukata, Tominaga, Murakami, Fukushima, Ebisui, Segawa, Nakao and Imura. Regu-

lation of interleukin-1 receptors on AtT-20 mouse pituitary tumour cells. FEBS Lett.

298: 100–104, 1992.

Kovacs and Elenkov. Differential dependence of ACTH secretion induced by various cytokines

on the integrity of the paraventricular nucleus. J. Neuro endocrinol. 7: 15–23, 1995.

Krueger and Majde. Cytokine and sleep. Int Arch Allergy Immunol.106 (2):97-100, 1995

Labow,Shuster,Zetterstom,Nunes,Terry,Cullinan,Bartfai,Solorzano,Moldawer,Chizzonite,Mcint

re. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I recep-

tor-deficient mice. J. Immunol. 159: 2452–2461, 1997.

Laye, Goujon, Combe, Vanhoy, Kelly, Parnet and Dantzer. Effects of lipopolysaccharide and

glucocorticoids on expression of interleukin -1 beta converting enzyme in the pituitary

and brain of mice. journal of Neuro immunology 68: 61–66, 1996.

Laye, Parnet, Goujon and Dantzer. Peripheral administration of lipopolysaccharide induces the

expression of cytokine transcripts in the brain and pituitaries of mice. Brain Research,

Molecular Brain Research. 27: 157–162, 1994.

Lechan, Toni, Clark, Cannon, Shaw, Dinarello and Reichlin. Immunoreactive interleukin-1β lo-

calization in the rat forebrain. Brain Res. 514: 135–140, 1990.

Lee and Rivier. Prenatal alcohol exposure alters the hypothalamic-pituitary-adrenal axis response

of immature offspring to interleukin-1: is nitric oxide involved? Alcohol. Clin. Exp. Res.

18:1242–1247, 1994.

Lewis, Tartaglia, Lee, Bennet, Rice, Wong, Chen and Goeddel. Cloning and expression of

cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor

is species specific. Proc. Natl. Acad. Sci. USA 88: 2830–2834, 1991.

Licinio, Wong and Gold. Localization of terleukin-1 receptor antagonist mRNA in rat brain.

Endocrinology 1991: 562–564, 1991.


Linthorst, Flachskamm, Holsboer and Reul. Local administration of recombinant human Inter-

leukin 1b in the rat hippocampus increases serotonergic neuro-transmission, hypotha-

lamic-pituitary-adrenocortical axis activity and body temperature. Endocrinology 135:

520–533, 1994.

Lissoni, Barni, Rovelli, Crispino, Fuma-Galli, Pescia, Vaghi, Camesasca and Tancini. Neuroen-

docrine effects of subcutaneous interleukin-2 injection in cancer patients. Tumor 77:

212–215, 1991.

Liu, Kita, Tanaka and Kinoshita. The expression of tumor necrosis factor in the hypothalamus

after treatment with lipopolysaccharide. Int. J. Exp. Pathol. 77: 37–44, 1996.

Lustig, Danenberg, Kafri, Kobiler and Ben-Nathan. Viral neuro invasion and encephalitis in-

duced by lipopolysaccharide and its mediators. J. Exp. Med. 176: 707–712, 1992.

Mackiewicz, Sollars, Ogilvie and Pack. Modulation of IL-1b gene expression in the rat CNS dur-

ing sleep deprivation. Neuroreport 7: 529–533, 1996.

Malarkey and Zvara. Interleukin-1β and other Cytokines stimulate Adrenocorticotropin release

from cultured pituitary cells of patients with Cushing’s disease. J. Clin. Endocrinol.

Metab. 69: 196–199, 1989.

Marquetee, Van dam, Can, Laniece, Cruarias, Fillion, Berkenbosch and Komaroff. Rat interleu-

kin-1b binding sites in rat hypothalamus and pituitary gland. Neuroendocrinology 62:

362–369, 1995.

Mastorakos, Chrousos and Weber. Recombinant interleukin-6 activates the hypothalamic-

pituitary-adrenal axis in humans. Journal of Clinical Endocrinology Metabolism 77:

1690–1694, 1993.

Matta, Linner and Sharp. Interleukin-1βand interleukin-1β stimulates Adrenocorticotropin secre-

tion in the rat through a similar hypothalamic receptor(s): effects of interleukin- 1 recep-

tor antagonist protein. Neuroendocrinology 57: 14–22, 1993.

Mazzocchi, Musajo, Malendowicz, Andreis and Nussdorfer. Interleukin-1b stimulates

corticotropin-releasing hormone (CRH) and Adrenocorticotropin (ACTH) release by rat

adrenal gland in vitro. Mol. Cell. Neurosci.79: 470–473, 1993.

Megyeri, Abraha, Temesvari, Kovacs, Vas and SPEER. Recombinant tumor necrosis factor α

constricts pial arterioles and increases blood-brain barrier permeability in newborn pig-

lets. Neurosci. Lett. 148: 137–140, 1992.


Minami, Kuraishi, Yamaguchi, Nakai, Hiral, and Satoh.Immobilization stress induces interleu-

kin-1b mRNA in the rat hypothalamus. Neuroscience Letter 123: 254–256.

Miyajima A, Kitamura T, Harada n, Yokota and Arai k. Cytokine receptors and signal transduc-

tion. Annual Review of Immunology 10: 295–331, 1992.

Muramami, Fukata, Tsukada, Kobayashi, Ebisui, Segawa, Muro, Imura and Nakao. Bacterial

lipopolysaccharide-induced expression of interleukin-6 messenger ribonucleic acid in

the rat hypothalamus, pituitary, adrenal gland, and spleen. Endocrinology 133: 2574–

2578, 1993.

Naito, Fukata, Tominaga, Masui, Hirai, Murakami, Tamai and Imura. Adrenocorticotropic hor-

mone releasing activities of interleukins in a homologous in vivo system. Biochem.

Biophys. Res. Commun. 164: 1262–1267, 1989.

O’Connell, Kumar, Chatzipanteli, Mohan, Agarwal, Head, Bornstein, Abou-Samaraand

Gwosdow.Interleukin-1 regulates corticosterone secretion from the rat adrenal gland

through a catechol amine-dependent and prostaglandin E2-independent mechanism. En-

docrinology 135: 460–467, 1994.

Ohmichi, Hirota, Koike, Kurachi, Ohtsuka, Matsuzaki, Yamaguchi, Miyake and Tanizawa Bind-

ing sites for interleukin-6 in the anterior pituitary gland. Neuroendocrinology 55: 199–

203, 1992.

Parnet, Brunke, Goujon, Desmottes-Mainard, Biragyn, Arkins, Dantzer and Kelley. Molecular

identification of two types of IL-1 receptors in the murine pituitary gland. J. Neuro

endocrinol. 5: 213–218, 1993.

Path and Bornstein. Interleukin-6 and interleukin receptor in the human adrenal gland: expres-

sion and effects on steroidogenesis. J. Clin. Endocrinol. Metab. 82: 2343–2349, 1997.

Pereda, Goldberg, Chevron, Carrizo, Molina, Andrada, Sauer, Renner, Stalla and Arzt. Interleu-

kin-2 (IL-2) and IL-6 regulate c-fos protooncogene expression in human pituitary ade-

noma explants. Mol. Cell. Endocrinol. 124: 33–42, 1996.

Perlstein, Mehta, Mougey, Neta and Whitnall. Systemically administered H1 and H2 receptor

antagonists do not block the ACTH response to bacterial lipopolysaccharide and inter-

leukin-1. Neuroendocrinology 60:418–425, 1994.


Pitossi, Del rey, Kabiersch and Besedovsky. Induction of cytokine transcripts in the CNS and

pituitary following peripheral administration of endotoxin to mice. J. Neurosci. Res. 48:

287–298, 1997.

Ray, Ren and Melmed. Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin

(POMC) expression in thalamo-pituitary-adrenal axis of the rat. Ann. NY Acad. Sci.

697:1852–1859, 1996.

Ray and Melmed. Pituitary cytokine and growth factor expression and action. Endocrine re-

view.18:206-228, 1997

Renner, Newton, Pagotto, Sauer, Arzt and Stalla. Involvement of interleukin-1 and interleukin-1

receptor antagonist in rat anterior pituitary cell growth regulation. Endocrinology 136:

3186–3193, 1995.

Rettori, Dees, Hiney, Lyson and McCann. An interleukin -1-alpha like neuronal system in the

preoptic hypothalamic region and its induction by bacterial lipopolysaccharide in con-

centrations which alter pituitary hormone release. Neuroimmunomodulation 1: 251–

258, 1994.

Reyes and Coe. Interleukin-1β differentially affects interleukin-6 and soluble interleukin-6 re-

ceptor in the blood and central nervous system of the monkey. J. Neuro immunol. 66:

135–141, 1996.

Rezai, Martinez-Maza, Vanderd Meyden and Weiss. Interleukin-6 and interleukin-6 receptor

gene expression in pituitary tumors. J. Neuro-oncol. 19: 131–135, 1994.

Ritchie, Knoght, Ashby and Judd. Serotonin increases interleukin-6 release and decreases tumor

necrosis factor release from rat adrenal zona glomerulosa cells in vitro. Endocrine 5:

291–297, 1996.

Rivest, Torres and Rivier. Differential effects of central and peripheral injection of interleukin-1β

on brain c-fos expression and neuroendocrine functions. Brain Res. 587: 13–23, 1992.

Rivier and Plotsky. Mediation by corticotropin-re leasing factor (CRF) of Adenohypophysial

hormone secretion. Annu. Rev. Physiol. 48: 475–494, 1986.

Rivier, Chizzonite and Vale. In the mouse, the activation of the hypothalamic-pituitary-adrenal

axis by a lipopolysaccharide (endotoxin) is mediated through interleukin-1. Endocrinol-

ogy 125: 2800–2805, 1989.


Roh, Drazenovich, Barbose, Dinarello and Cobb. Direct stimulation of the adrenal cortex by in-

terleukin-1. Surgery 102: 140–146, 1987.

Salas, Evans, Levell and Whicher. Interleukin-6 and ACTH act synergistically to stimulate the

release of corticosterone from adrenal gland cells. Clinical Experiment of Immunology

79: 470–473, 1990.

Saphier and Ovadia. Selective facilitation of putative corticotropin-releasing factor-secreting

neurons by interleukin-1.Neuroscience Letter 114: 283–288, 1990.

Sapolsky, Rivier, Yamamoto, Plotsky and Vale. Interleukin-1 stimulates the secretion of hypo-

thalamic corticotropin-releasing factor. Science 238: 522–524, 1987.

Sarlis, Stephanou, Knight, Lightman and Chowdrey. Effects of glucocorticoids and chronic in-

flammatory stress upon anterior pituitary interleukin-6 mRNA in the rat. Br. J.

Rheumatol. 32: 653–657, 1993.

Sato and Miyajima. Multimeric cytokine receptor: Common versus specific function. Curr Opin

Cell Biol. 6(2):174-9, 1994

Scaccianoce, Cigliana, Nicolai, Musculo, Porcu, Navarra, Perez-Polo and Angelucci. Hypotha-

lamic involvement in the activation of the pituitary-adrenocortical axis by nerve growth

factor. Neuroendocrinology 58: 202–209, 1993.

Schmidt, Janszen, Wouterlood and Tilders. Interleukin-1-induced long-lasting changes in hypo-

thalamic corticotropin-releasing hormone (CRH)-neurons and hyper responsiveness of

the hypothalamus-pituitary-adrenal axis. J. Neurosci. 15: 7417–7426, 1995.

Schobitz, De kloet, Sutanto and Holsboer. Cellular localization of interleukin-6 mRNA and inter-

leukin-6 receptor mRNA in rat brain. Eur. J. Neurosci. 5: 1426–1435, 1993.

Schultzberg, Tingsborg, NobeL, Lundkvist, Svenson, Simoncsits and Bartfai. Interleukin-1 re-

ceptor antagonist protein and mRNA in the rat adrenal gland. J. Interferon Cytokine Res.

15: 721–729, 1995.

Sharif, Hairi, Chang, Barie, Wang, and Ghajar. Human astrocyte production of tumor necrosis

factor-alpha, interleukin-1 beta, and interleukin-6 following exposure to lipopolysaccha-

ride endotoxin. Neurol. Res. 15: 109–112, 1993.

Shimon, Yan, Ray and Melmed. Human fetal pituitary cells express functional gp130-related cy-

tokine-specific receptors: regulation of ACTH and growth hormone secretion. Proc.

Annu. Meet. Endocr. Soc. 79th Minneapolis.1997.


Shintani, Nakai, Kanba, Kato and Asai. Role of interleukin-1 in stress responses. A putative neu-

rotransmitter. The toxic and hematologic effects of interleukin-1 alpha Mol. Neurobiol.

10: 47–71, 1995.

Shizuya, Komori, Fujiwara, Miyahara, Ohmori and Nomura. The influence of restraint stress on

the exposure of mRNAs for IL-6 and the IL-6 receptor in the hypothalamus and mid-

brain of the rat. Life Sci. 61: 135–140, 1997

Shohami, Bass, Wallach, Yamin and Gallily. Inhibition of tumor necrosis factor alpha (TNFα)

activity in rat brain is associated with cerebroprotection after closed head injury. Journal

Cerebral Blood Flow Metab. 16: 378–384, 1996.

Shukla, Dikshit and Srimal. Nitric oxide modulates blood-brain barrier permeability during in-

fections with an activated bacterium. Neuroreport 6: 1629–1632, 1995.

Simon and Polan: Cytokines and reproduction. West journal Medicine. 160:425-429, 1994

Smith,Urba,Curti,Elwood,Steis,Janik,Sharfman,Miller,Fenton,Conlon,Sznol,Creekmore,Wells,R

uscetti,keller,Hestdal,Shimuzu,Rossio,Galvord,Oppenheim and Longo. The toxic and

hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with

advanced malignancies. Journal of Clinical Oncology 10: 1141–1152, 1992.

Spangelo and Gorospe. Role of cytokines in the neuroendocrine-immune system axis. Front.

Neuro endocrinol. 16:1–22, 1995.

Spangelo, Jarvis, Judd and Macleod. Induction of interleukin-6 release by interleukin-1 in rat an-

terior pituitary cells in vitro: evidence for an eicosanoid-dependent mechanism. Endo-

crinology 129: 2886–2894, 1991.

Stefana, Ray and Melmed. Leukemia inhibitory factor induces differentiation of pituitary

corticotroph function: an immuno-neuroendocrine phenotypic switch. Proc. Natl. Acad.

Sci. USA 93: 12502–12506, 1996.

Stepien, Zerek-Mefen, Mucha, Winczyk and Fryczak. Interleukin-1b stimulates cell proliferation

in the intermediate lobe of the rat pituitary gland. J. Endocrinol. 140: 337–341, 1994.

Suzuki, Shintani, Kanba, AsaI and Nakaki. Immobilization stress increases levels of interleukin-

1 receptor antagonist in various rat brain regions. Cell. Mol. Neuro biol. 17:557–562,

1997.


Szafarczyk, Guillaume, Conte-Devox, Aloenso, Malaval, Pares-Herbute, Oliver and

Assenmacher. Central catecholaminergic system stimulates secretion of CRH at differ-

ent sites. American Journal of Physiology 255 (Endocrinology Metabolism 18): E463–

E468, 1988.

Tadamitsu Kishimoto, Shizuo Akira, Masashi Narazaki, and Tetsuya Taga. Interleukin-6 Family

of Cytokines and gp130.Blood 86(4) August 15, 1995.

Taishi, Bredown, Guha -Thakurta, Obal and Krueger. Diurnal variations of interleukin-1β

mRNA and β-actin mRNA in rat brain. J. Neuroimmunol. 75: 69–74, 1997.

Takao, Culp, Newton and De souza. Type I interleukin-1 receptors in the mouse brain-endocrine-

immune axis labeled with [125I] recombinant human interleukin-1 receptor antagonist.

J. Neuroimmunol. 41: 51–60, 1992.

Take, Kanemitsu, Yasaka, Katafuchi, Hori and Eckenstein. Immobilization stress modulates the

expression of interferon-g mRNA in the mouse (Abstract). Proc.Annu. Meet. Soc.

Neurosci. 26th Washington DC. 336. 18, 1996.

Tatsuno, Somogyvari-Vigh, Mizuno, Gottschall, Hidaka and Arimura. Neuropeptide regulation

of interleukin-6 production from the pituitary: stimulation by adenylate cyclase activat-

ing polypeptide and calcitonin gene related peptide. Endocrinology 129: 1797–1804,

1991.

Tingsborg, Zetterstrom, Alheim, Hasanvan, Schultzberg and Bartfai. Regionally specific induc-

tion of ICE mRNA and enzyme activity in the rat brain and adrenal gland by LPS. Brain

Res. 712: 153–158, 1996.

Tominaga, Fukata, Naito, Usui, Murakami, Fukushima, Nakai, Hirai and Imura. Prostaglandin-

dependent in vitro stimulation of adrenocortical steroidogenesis by interleukins. Endo-

crinology 128: 526–531, 1991.

Toshio Kitamura, Toshiya Ogorochi and Atsushi Miyajima: Multimeric cytokine receptors.

Trends in Endocrinology and Metabolism.5 (1) 8-14, 1994.

Tracey and De souza. Identification of interleukin-1 receptors in mouse pituitary cell membranes

and AtT-20 pituitary tumor cells. Soc. Neurosci. Abstr. 14: 1052, 1988.

Tunkel, Rosser, Hansen and Scheld. Blood-brain barrier alterations in bacterial meningitis: de-

velopment of an in vitro model and observations on the effects. Lipopolysaccharide. In

Vitro Cell. Dev. Biol. 27: 113–120, 1991.


Turnbull and Rivier. Corticotropin-releasing factor (CRF) and endocrine responses to stress:

CRF receptors, binding protein and related peptides. Proc. Soc. Exp. Biol. Med. 215: 1–

10, 1997.

Turnball and Rivier. Regulation of the Hypothalamic Pituitary Adrenal Axis by Cytokines: Ac-

tions and Mechanisms of Action. Physiology Review 79:1-71, 1999.

Vallieres and Rivest. Regulation of the genes encoding interleukin-6, its receptor, and gp130 in

the rat brain in response to the immune activator lipopolysaccharide and the

proinflammatory cytokine interleukin-1β. Journal of Neuro chem. 69: 1668–1683, 1997.

Van Der Meer, Sweep, Pesman, Tilders and Hermus. Chronic Stimulation of the Hypothalamus

Pituitary Adrenal Axis in Rats by Interleukin β: Central and Peripheral Mechanisms. Cy-

tokine 8: 910–919, 1996.

Velkeniers, Vergani, Trouillas, D’haens, Hooghe-Peters. Expression of IL-6 mRNA in normal

rat and human pituitaries and in human pituitary adenomas. J. Histochem. Cytochem. 42:

67–76, 1994.

Vellucci, Parrot, Costa, Ohkura and Kendrick. Increased body temperature, cortisol secretion,

and hypothalamic expression of c-fos, corticotropin releasing hormone and interleukin-

1β, following central administration of interleukin-1βin the sheep. Brain Res. 29: 64–70,

1995.

Vera Chesnokova and Shlomo Melmed, Neuro-Immuno-Endocrine Modulation of the Hypotha-

lamic-Pituitary-Adrenal (HPA) Axis by gp130 Signaling Molecules. Endocrinology.

143(5):1571–1574, May 2002.

Vitkovic Ljubisa, Bockaert Joel and Jacque Claude. “Inflammatory” cytokines: Neuromodulators

in Normal Brain? Journal of Neurochemical. 74, 457–471, 2000.

Watanabe, Morimoto and Murakami. ACTH response in rats during biphasic fever induced by

interleukin-1. American Journal of Physiology 261 (Regulatory Integrative Comp.

Physiol. 30) 1104–R1108, 1991.

Watanobe and Takebe. Intravenous administration of tumor necrosis factor- α stimulates

corticotropin-releasing hormone secretion in the push-pull cannulated median eminence

of freely moving rats. Neuropeptides 22: 81–84, 1992.


Whitnall, Perlstein, Mougey and Neta. Effects of interleukin-1 on the stress-responsive and non-

responsive subtypes of corticotropin-releasing hormone neuro secretory axons. Endocri-

nology 131: 37–44, 1992.

Wick, Schwarz and Kroemer. Immuno endocrine communication via the hypothalamo-pituitary-

adrenal axis in autoimmune diseases. Endocrine Review 14: 539–563, 1993.

Winter, Gow, Perry and Greenberg. A stimulatory effect of interleukin-1 on adrenocortical corti-

sol secretion mediated by prostaglandins. Endocrinology 127: 1904–1990, 1990.

Woloski, Smith, MeyerIII, Fuller and Blalock. Corticotropin-releasing activity of Monokines.

Science 230: 1035–1037, 1985.

Wolvers, Marquette, Berkenbosch and Haour. Tumor necrosis factor-alpha: specific binding sites

in rodent brain and pituitary gland. Eur. Cytokine Netw. 4: 377–381, 1993.

Yabuuchi, Maruta, Minami and Satoh. Induction of interleukin -1b mRNA in the hypothalamus

following subcutaneous injections of formalin into the rat hind paws. Neuroscience Let-

ter 207: 109–112, 1996.

Yao and Johnson. Induction of interleukin-1 beta converting enzyme (ICE) in murine microglia

by lipopolysaccharide. Brain Research 51: 170–178, 1997.

Younis and Abou El-Ezz. How Do Cytokines Influence Stress Responses? Animal Physiology

Department, Animal and Poultry Division, Desert Research Center, Egypt.2010

Zieleniewski and Stepien. Effect of interleukin-1a, IL-1b and IL-1 receptor antibody on the pr

liferation and steroidogenesis of regenerating rat adrenal cortex. Exp.Clin.

Endocrinol. Diabetes 103: 373–377, 1995.

Ziemssen and Kern, Psycho neuro immunology Cross talk between the immune and nervous sys-

tems, Journal of Neurology, 254 (2007)

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Regulations of hpa by cytokines