BBRCjohnjhaddad.weebly.com/uploads/2/5/2/0/2520519/bbrc... · 2018. 10. 2. · signaling peptide messengers, which act essentially be-tween immune cells that coordinate the inﬂammatory

Breakthroughs and Views

Cytokines and related receptor-mediated signaling pathways

John J. Haddad*

Severinghaus-Radiometer Research Laboratories, Molecular Neuroscience Research Division, Department of Anesthesia and Perioperative Care,

School of Medicine, University of California at San Francisco, Medical Sciences Building S-261,

513 Parnassus Avenue, San Francisco, CA 94143-0542, USA

Received 29 August 2002

Abstract

Cytokines represent a multi-diverse family of polypeptide regulators; they are of relatively low molecular weight, pharma-

cologically active proteins that are secreted by one cell for the purpose of altering either its own functions (autocrine effect) or

those of adjacent cells (paracrine effect). Cytokines are small, non-enzymatic glycoproteins whose actions are both diverse and

overlapping (specificity/redundancy) and may affect diverse and overlapping target cell populations. In many instances, indi-

vidual cytokines have multiple biological activities. Different cytokines can also have the same activity, which provides for

functional redundancy within the inflammatory and immune systems. As biological cofactors that are released by specific cells,

cytokines have specific effects on cell–cell interaction, communication, and behavior of other cells. As a result, it is infrequent

that loss or neutralization of one cytokine will markedly interfere with either of these systems. The biological effect of one

cytokine is often modified or augmented by another. Because an inter-digitating, redundant network of cytokines is involved in

the production of most biological effects, both under physiologic and pathologic conditions, it usually requires more than a

single defect in the network to alter drastically the outcome of the process. This fact therefore may have crucial significance in

the development of therapeutic strategies for bio-pharmacologic intervention in cytokine-mediated inflammatory processes and

infections.

� 2002 Elsevier Science (USA). All rights reserved.

Keywords: Apoptosis; Cytokine; Immunopharmacology; Network; Neuroimmunology; Receptor; Transcription factors

Cytokines are soluble mediators of inter- and intra-cellular communications [1–6]. They contribute to achemical signaling language that regulates development,tissue repair, hemopoiesis, inflammation, and the spe-cific and non-specific immune responses. Potent cyto-kine polypeptides have pleiotropic activities andfunctional redundancy; in fact, they act in a complex,intermingled network where one cytokine can influencethe production of, and response to, many other cyto-kines [7–13]. In the past few decades, this bewildering,burgeoning array of more than 100 effector moleculesand associated cell surface receptors has been simplifiedby the study of cytokines and their receptors, the elu-cidation of convergent intracellular signaling pathwaysand molecular genetics, and the targeted gene disruptionto �knock-out� production of individual inflammatory

mediators [14–21]. It is also now clear that the patho-physiology of infectious, autoimmune, and malignantdiseases can be explained, at least in part, by the in-duction of cytokines and the subsequent protractedcellular responses [22–30]. Viral homologs, for instance,exist for many cytokines and receptors and geneticvariations in cytokine production may influence the re-sponse to many pathogenic stimuli. Of note, cytokinesand cytokine antagonists have also exhibited therapeuticpotential in a number of chronic and acute diseases.This paper comprehensively overviews the field of cy-tokine research and describes the various approachesthat have been undertaken to date to develop a scenariofor the molecular regulation of the pharmacology ofthese novel mediators. Since the pharmacology of cy-tokines is an exploding area that is rapidly invading theclinical arena, this review will elaborate on the frame-work of the immunobiology of cytokines and examinethe interactions within the cytokine milieu. In addition

Biochemical and Biophysical Research Communications 297 (2002) 700–713

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to examining individual agents and approaches, thepaper examines receptor-related signaling pathways inthe network of cytokine research and medicine.

Inflammatory cytokines as putative regulators of a

plethora of cellular functions

The evolution of the inflammatory process: an overview

Inflammation is the process by which the humanbody attempts to counteract potentially injurious agentssuch as invading bacteria, viruses, and other pathogens[31–33]. Although it is essential, inflammation can beharmful to the host and therefore it is subject to multiplelevels of biochemical, pharmacological, and molecularcontrols involving a diverse and potentially huge arrayof cell types and soluble mediators including cytokines(Fig. 1) [1–4,34]. Cytokines are autocrine and paracrinesignaling peptide messengers, which act essentially be-tween immune cells that coordinate the inflammatoryresponse across time and space, temporally and spatially[1–6]. Specific signals, including those of an infectiousorigin such as virulent and avirulent microorganisms(lipopolysaccharide-endotoxin (LPS) derived fromGram-negative bacteria [35–38] and superantigens ofGram-positive bacteria [39–43]), stimulate host cells tosecrete pro-inflammatory mediators (cytokines/chemo-kines), which recruit, alert, and activate neighboringcells necessary for mounting an effective immune re-sponse (Fig. 2) [1–4,33]. Therefore, cytokines play apivotal role in influencing the nature, extent, and con-sequences of inflammation. Tissue repair mechanisms byregeneration versus fibrosis as prompted by damage or

an ensuing inflammatory response are depicted in Fig. 3to stress the role of cytokines in the evolution and per-petuation of the inflammatory reaction.

The nomenclature, nature, and biochemistry of cytokines:general aspects

Cytokines are small, non-structural proteins origi-nally called lymphokines and monokines, solely to in-dicate their cellular sources from lymphocytes andmonocytes, respectively [1–4,44]. The cytokine networkcomprises a large and multi-diverse family of polypep-tides that are produced throughout the body of cells ofassorted embryological origin [44,45]. In general, theseregulatory peptides have multiple functions attributableto specific actions when evaluated under controlledconditions in vitro [1–6,44,45]. The effects of cytokinesare known to be further regulated by the conditionsimposed by other simultaneously acting cytokines, in-teracting as a network with variable effects culminatingin the activation of synergistic, additive or even oppos-ing and contrasting (antagonistic) actions in vivo (Fig.4) [1–6,46,47]. Although small amounts of certain cy-tokines remain associated with the cell membrane of theproducing cell, most cytokines are immediately releasedinto the surrounding interstitial (extracellular) fluidupon biosynthesis (secretion) [34,48–50]. The term �im-munocytokines� was used initially to separate a group ofimmunomodulatory proteins (called also immuno-transmitters) from other growth factors that modulatethe proliferation/bioactivity of non-immune cells [1–4].However, this terminology suggests that a clear-cutdistinction cannot be maintained and may not bemeaningful altogether. Some cytokines, for example, are

Fig. 1. Summary schematic of tissue inflammation, injury, and repair.

J.J. Haddad / Biochemical and Biophysical Research Communications 297 (2002) 700–713 701

produced by a rather limited number of different celltypes while others are produced by almost the entirespectrum of known cell types [5,6]. The initial concept of�one producer cell-one cytokine-one target cell� has been

scrutinized for almost every cytokine investigated moreclosely [4,5]. A definition of these factors on the basis oftheir producer or target cells is therefore also problem-atic. The same applies to classifications based upon

Fig. 3. Tissue repair by regeneration versus fibrosis as prompted by damage or an inflammatory response.

Fig. 2. Schematic drawing of eosinophil recruitment to the site of an inflammatory reaction. (1) Tissue cells, e.g., lymphocytes (Ly) or macrophages

(Mø), stimulate endothelial cells in postcapillary venules to express surface adhesion molecules on their surface. (2) Initially, the cell is ‘‘marginated’’

in the blood vessel and starts ‘‘rolling’’ along the endothelium, a process mediated by adhesion molecules of the selectin type. (3) The eosinophil

granulocytes are activated, in particular by inflammatory mediators released by the endothelial cells, and subsequently bind strongly to the endo-

thelial cells. This firm binding is mediated through b1- and b2-integrins. The activation of b2-integrins also causes a shape change and the eosinophilbecomes flattened. (4) Several inflammatory mediators produced at the site of inflammation stimulate the eosinophil granulocytes to leave the blood

vessel, using its b1- and b2-integrins, and enter the tissue where it exerts its function.

702 J.J. Haddad / Biochemical and Biophysical Research Communications 297 (2002) 700–713

identical or shared biological activities of cytokines es-pecially with broad definitions [51]. Today, the term�cytokine� is largely used as a generic name for a diversegroup of soluble peptides that act as humoral regulatorsat nano- to picomolar concentrations and which, eitherunder normal or pathological conditions, modulate thefunctional activities of individual cells and tissues [1–6].These proteins also mediate interactions between cellsdirectly and regulate processes taking place in the ex-tracellular environment (Fig. 5) [7–12,52]. For instance,many growth factors and cytokines act as cellular sur-vival factors by preventing programmed cell death orapoptosis. In many respects, the biological activities ofcytokines resemble those of classical hormones pro-duced in specialized glandular tissues. Some cytokinesalso behave like classical hormones in that they act at asystemic level, affecting, for example, biological phe-nomena such as inflammation, septic shock, and acutephase reaction, wound healing, and the neuroimmunenetwork [7–12,53–56]. In general, however, cytokines acton a wider spectrum of target cells than hormones.Perhaps, the major feature distinguishing cytokinesfrom mediators regarded generally as hormones is thefact that, unlike hormones, cytokines are not producedby specialized cells, which are organized in specialized

glands; that is, there is not a single organ source forthese mediators [53–56]. The fact that cytokines are se-creted proteins also means that the sites of their ex-pression do not necessarily predict the sites at whichthey exert their biological function. Although cytokinesnormally do not possess enzymatic activities, some cy-tokines, for instance, have been found, upon determi-nation of their primary structures, to be identical withclassical enzymes [1–6,8–12,51–56]. The biological ac-tivity of cytokines can be measured by a variety ofbioassays employing, among other things, factor-de-pendent cell lines, or by other assays using, for example,mono- or polyclonal antibodies [57–63]. Reverse tran-scription polymerase chain reaction (RT-PCR) quanti-tation of cytokines, for example, employs moderntechniques of molecular biology and detects the presenceof mRNA encoding specific cytokines [64–66].

In the more restricted sense, cytokines comprise in-terleukins (initially thought to be produced exclusivelyby leukocytes), lymphokines (initially thought to beproduced exclusively by lymphocytes), monokines (ini-tially thought to be produced exclusively by monocytes),interferons (initially thought to be involved in antiviralresponses), colony-stimulating factors (initially thoughtto support the growth of cells in semisolid media),

Fig. 4. The burgeoning and closely entangled cytokine network.


chemokines (thought to be involved in chemotaxis), anda variety of other proteins (Table 1). The term type-1cytokines refers to cytokines produced by type-1 helpercells while type-2 cytokines are those produced by type-2helper cells [67–74]. Type-1 cytokines include, for in-stance, interleukin (IL)-2, interferon (IFN)-c, IL-12, andtumor necrosis factor (TNF)-b, while type-2 cytokinesinclude IL-4, IL-5, IL-6, IL-10, and IL-13. Most cyto-kines are unrelated in terms of sequence, although somecan be grouped into families or are classified into cate-gories according to the types of secondary and tertiarystructure. IFN-a, IFN-b, IFN-X, IL-2, IL-3, IL-4, IL-5,IL-6, IL-7, IL-9, G-CSF, M-CSF, GM-CSF, andPDGF, for example, have a-spiral secondary structure.b-Structural cytokines include IL-1a, IL-1b, TNF-a,TNF-b, and FGF. Composite structures (a þ b) areobserved with IL-8, IFN-c, IP-10, PF-4, GRO, and 9E3(Table 2; Fig. 6). According to the type of tertiarystructure, a-spiral proteins can be grouped further intoIFN-like and IL-2-like families, and b-structural pro-teins can be grouped into IL-1-like and TNF-like fam-ilies. Furthermore, many genes encoding cytokines cangive rise to a variety of variant forms of cytokines bymeans of alternative splicing thereby yielding moleculeswith biologically significant, but slightly different, bio-

activities. In many cases, the expression patterns ofdifferent forms of cytokines are overlapping only par-tially, suggesting a specific role for each cofactor [1–6].Membrane-bound forms have been described also formany cytokines and some may be associated also withthe extracellular matrix. It is likely therefore that theswitching between soluble and membrane forms of cy-tokines is an important regulatory event (autocrine,paracrine, juxtacrine, and retrocrine). In some cases,membrane forms of a cytokine have been found to beindispensable for normal development, with solubleforms being unable to entirely substitute for them. Mostcytokines are generally not stored inside cells (excep-tions are, for example, TGF-b and PDGF, both ofwhich are stored in platelets) and are promptly secretedusing classical secretory pathways. Schematic overviewof the concept of cytokine redundancy and receptorspecificity is depicted in Fig. 6.

The biology and pharmacology of cytokines

The expression of most cytokines is strictly regu-lated—these factors are usually produced only by acti-vated cells in response to an induction signal

Fig. 5. The potential pathways in cytokine networking.


Table 1

Functional pharmaco-biochemical properties of some major cytokines

Cytokine Molecular form

MW (kDa)

Source Major functions

Interleukin-1 a=b(IL-1a=b)

Monomers 159 and

153 aa, respectively;

Monocytes/macrophages, endothelial cells,

fibroblasts, neuronal cells, glial cells,

keratinocytes, epithelial cells, dendritic

cells, NK cells, T-cells, and B-cells

Locally IL-1 affects cells involved in

inflammation, injury, or infection

17.5 and 17.3,

respectively

Systemically IL-1 causes fever, hypertension,

and shock

Interleukin-2 (IL-2) Monomer 133 aa T-cells Stimulates growth and differentiation of

T-cells, B-cells, NK-cells, LAK-cells,

monocytes, macrophages, and

oligodendrocytes

15–20

Interleukin-3 (IL-3) Monomer 133 aa T-cells, mast cells, and eosinophils Stimulates colony formation of several cell

types

14–30

Interleukin-4 (IL-4) Monomer 129 aa T-cells, mast cells, bone marrow, and

stromal cells

In humans, IL-4 induces the proliferation

and isotype switching of B cells to IgG4

and IgE

15–19 Induces the differentiation of naive CD4 T

cells into T-helper-2-like cells

Interleukin-5 (IL-5) Homodimer 115 aa T-cells, mast cells, and eosinophils Stimulates the proliferation and differentiation

of eosinophils

45 (homodimer)

Interleukin-6 (IL-6) Monomer 183 aa T-cells, B-cells, monocytes/macrophages,

fibroblasts, hepatocytes, endothelial cells,

keratinocytes, bone marrow, and stromal

cells

IL-6 is a functional multi-cytokine which

regulates T- and B-cell functions,

hematopoiesis, and acute phase reactions

26

Interleukin-7 (IL-7) Monomer 152 aa Bone marrow, stromal cells, thymic stromal

cells, and spleen cells

IL-7 is a growth factor for progenitor B- and

T-cells, especially CD4 CD8 cells

20–28 Stimulates proliferation and differentiation

of mature T-cells

Interleukin-8 (IL-8) Dimer 72–77 aa Monocytes, T-cells, fibroblasts, endothelial

cells, keratinocytes, hepatocytes,

chondrocytes, neutrophils, and epithelial

cells

Functions as a neutrophil chemoattractant

and activating factor

6–8 Attracts basophils and lymphocytes

IL-8 is a potent angiogenic factor

Interleukin-9 (IL-9) Monomer 126 aa T-cells Enhances the proliferation of T-lymphocytes,

mast cells, megakaryoblastic leukemia cell

lines, and erythroid precursors

32–39

Interleukin-10 (IL-10) Homodimer 179 aa T-cells, monocytes/macrophages,

keratinocytes, and B-cells

Blocks activation of cytokine synthesis by TH1

cells, activated monocytes, and NK-cells

35–40 Stimulates and/or enhances proliferation of

B-cells, thymocytes, and mast cells

In co-operation with TGF-b, IL-10stimulates IgA production by human B-cells

Interleukin-11 (IL-11) Monomer 179 aa Stimulated fibroblasts, bone marrow

stromal cell lines

IL-11 is a growth factor for plasmacytomas,

hematopoietic multipotential, and committed

megakaryocytic and macrophage progenitor

cells

23

Interleukin-12 (IL-12) Heterodimer of p35:

196 aa and p40: 306 aa

B-cells and monocytes/macrophages Induces IFN-c production by T-cells andNK-cells

Enhances NK and ADCC activity


[4,6,20,32,34,44,52,54,67,72,73]. Cytokine expression isnormally transient and can be regulated at all levels ofgene expression (transcriptional/translational). How-ever, constitutive expression has been observed also. Theexpression of many cytokines also seems to be regulateddifferentially, depending on cell type and developmentalage [2,7,9,45,55]. Most cytokines were detected initially

in functional tests in vitro as bio-chemically undefinedactivities or as distinct factors with distinct biologicalactivities [1–6]. This also explains, at least in part, theplethora of different names for some of the cytokines. Inmany instances, these activities were named after aparticular biological activity observed in an in vitro as-say or after cells that were found to elaborate these

Table 1 (continued)

Cytokine Molecular form

MW (kDa)

Source Major functions

Co-stimulates peripheral blood lymphocyte

proliferation

p35: 30–33 and p40:

35–44

Stimulates proliferation and induces the

differentiation of TH1-cells

Interleukin-13 (IL-13) Monomer 132 aa T-cells Induces B-cell growth and differentiation

9/17 Inhibits inflammatory cytokine production

by monocytes/macrophages

Induces CD23 expression on human B-cells

and stimulates secretion of IgM, IgE, and IgG4

Prolongs survival of human monocytes

Interleukin-14 (IL-14) Monomer 483 aa T-cells Enhances proliferation of activated B-cells

60 Inhibits immunoglobulin synthesis

Interleukin-15 (IL-15) Monomer 114 aa Monocytes and epithelial cells Stimulates proliferation of T-cells and

LAK-cells

14–15

Interferon a=b (IFNa=b) Monomer, manya species (90%homologous) have

been identified

T-cells, B-cells, monocytes/macrophages,

fibroblasts, and some epithelial cells

Anti-viral activity

a 165/166 aa Stimulates macrophages and NK-cell activityb 166 aa Modulates MHC class I expressiona 16–27 Anti-tumoral activityb 20

Interferon c (IFNc) Homodimer 143 aa T-cells and NK- cells Is involved in the regulation of nearly allphases of immune and inflammatory responses

40–70 Has weak anti-viral and anti-proliferative

activity

Potentiates the anti-viral and anti-tumoral

effects of IFN a=b

IFN X Monomer 172/174 aa Leucocytes Anti-viral activity25 Anti-tumoral activity

Modulates MHC class I expression

Tumor necrosis factor a(cachectin) (TNFa)

Trimer 157 aa Monocytes/macrophages, T-cells, B-cells,

fibroblasts, neutrophils, NK-cells,

LAK-cells, and endothelial cells

TNF a is a potent paracrine and endocrinemediator of inflammatory and immune

functions, including B-cell, T- cell, and

macrophage and neutrophil activities

52 Regulates growth and differentiation of a

wide variety of cell types

Tumor necrosis factor b(lymphotoxin) (TNFb)

Trimer 171 aa (after

removal of predicted

signal peptide)

T-cells and B-cells TNF b is a potent paracrine and endocrinemediator of inflammatory and immune

functions, including B-cell, T-cell, and

macrophage and neutrophil activities

25 (corresponds to the

submit secreted by

RPMI1788, the

20 kDa TNFbsecreted, is a

breakdown product)

Regulates growth and differentiation of a wide

variety of cell types


factors. One should be aware, however, of the fact thatat this moment in time the relevance of many in vitroactivities of cytokines to their endogenous functionswithin an intact organism is not clearly defined. Almostall cytokines are pleiotropic effectors showing multiplebiological activities. In addition, multiple cytokines of-ten have overlapping activities and a single cell fre-quently interacts with multiple cytokines with seeminglyidentical responses (cross-talk) [67,68]. One of the con-sequences of this functional overlap is the observationthat one factor may frequently functionally replace an-other factor altogether or, at least partially, compensatefor the lack of another factor. Since most cytokines haveubiquitous biological activities, their physiologic signif-icance as normal regulators of physiology is often diffi-cult to assess. Studies of gene functions in experimentaltransgenic animals in which a cytokine gene has beenfunctionally inactivated by gene targeting are of partic-ular importance in research on cytokines because, unlikein vitro studies, they provide information about the truein vivo functions of a given cytokine by highlighting the

effects of their absence [6,12,14,17,21]. In many in-stances, these studies have shown that null mutations(knock-out) of particular cytokine genes do not have theeffects in vivo expected from their activities in vitro.Furthermore, many cytokines show stimulating or in-hibitory activities and may synergise or antagonize alsothe actions of other factors. A single cytokine may elicitreactions also under certain circumstances, which arethe reverse of those shown under other circumstances.The type, the duration, and also the extent of cellularactivities induced by a particular cytokine can be influ-enced considerably by the micro-environment of a cell,depending, for example, on the growth state of the cells(sparse or confluent), the type of neighboring cells (in-tercellular communication), cytokine concentrations,the combination of other cytokines present at the sametime, and even on the temporal sequence of several cy-tokines acting on the same target cell [1–12]. The factthat every cell type may have different responses to thesame growth factor can be explained, at least in part, bydifferent spectrums of genes expressed in these cells and

Table 2

Structural families of cytokines and cytokine receptors

Cytokine family Members Receptor type

Haematopoietins (four a-helical bundles) IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-13, G-CSF,GM-CSF, CNTF, OSM, LIF, and EPO

Cytokine receptor class I

IL-10, IFN-a, IFN-b, and IFN-c Cytokine receptor class IIM-CSF Tyrosine kinase

EGF (b-sheet) EGF and TGF-a Tyrosine kinase

b-Trefoil FGF-a and FGF-b Split tyrosine kinaseIL-1a, IL-1b, and IL-1ra IL-1 receptor

TNF (Jelly roll motif) TNF-a, TNF-b, LT-b NGF/TNF receptor

Cysteine knot NGF NGF/TNF receptor

TGF-b1, TGF-b2, TGF-b3 Serine/threonine kinasePDGF and VEGF Tyrosine kinase

Chemokines (triple-stranded, anti-parallel b-sheet inGreek key motif)

IL-8, MIP-1a, MIP-1b, MIP-2, PF-4, PBP, I-309/TCA-3, MCP-1, MCP-2, MCP-3, cIP-10

Rhodopsin superfamily

Fig. 6. (A) Schematic view of the domain structure of non-chemokine, cytokine receptors. (B) Schematic view of the concept of cytokine redundancy:

receptor specificity results from the use of different chains but signal transduction is mediated by a common b chain.


the availability and levels of various transcription fac-tors that drive gene expression. Although a variety ofcytokines are known to share at least some biologicaleffects, the observations that single cells usually showdifferent patterns of gene expression in response to dif-ferent cytokines can be taken as evidence for the exis-tence of cytokine receptor-specific signal transductionpathways [55–74]. Shared and different transcriptionalactivators that transduce a signal from a cytokine re-ceptor to a transcription regulatory element of DNA areinvolved in these processes (STAT proteins and Januskinases). It has been observed, for example, that b-FGFis a strong mitogen for fibroblasts at low concentrationsand a chemoattractant at high concentrations[62,63,65,66]. BFGF has been shown also to be a bi-phasic regulator of human hepatoblastoma-derivedHepG2 cells, strictly depending upon concentration [1–6,72–74]. Moreover, IFN-c can stimulate the prolifera-tion of B-cells pre-stimulated with anti-IgM and inhibitsthe activities of the same cells induced by IL-4 [68–74].On the other hand, IL-4 activates B-cells and promotestheir proliferation while inhibiting the effects induced byIL-2 in the same cells (Table 1). Furthermore, the ac-tivity of at least two cytokines (IL-1a and IL-1b) isregulated by an endogenous receptor antagonist, the IL-1 receptor antagonist (IL-1ra). Several cytokines, in-cluding TNF, IFN-c, IL-2, and IL-4, are inhibited bysoluble receptors. In contrast, several cytokines, in-cluding IL-10 and TGF-b, act to inhibit other cytokinesand their bioactivities [1–12,55–74] (Tables 1 and 2).

The complex network of molecular processes re-sponsible for the regulation of cytokines is not wellunderstood. Cells use distinct biochemical pathwaysconverging on mediator release and these can be probedby employing a variety of substances mimicking or in-hibiting the actions of cytokines [75–80]. Frequently,one observes a hierarchical order of cytokine actionswith some early cytokines pre-activating cells so thatthey then can respond to late-acting cytokines. Manycytokines induce the synthesis of novel gene productsonce they have bound to their respective receptors; someof the novel products are themselves cytokines[28,54,55,67,68]. In addition, there are a variety of bio-logical response modifiers that function as anti-cyto-kines. Cytokine mediators can be transported quickly toremote areas of a multicellular organism. They can ad-dress multiple target cells and can be degraded quickly.For instance, concentration gradients can be used toelicit specific responses. These possibilities by far exceedthe possibilities provided by mere cell-to-cell contactswithin a multicellular organism. It can be assumedtherefore that cytokines play a pivotal role in all sorts ofcell-to-cell communication processes, although many ofthe mechanisms of their actions have not yet been elu-cidated in comprehensive detail [1–12]. A close exam-ination of the physiologic and pathologic effects of the

regulated or deregulated expression of cytokines incomplex organisms has shown that these mediators areinvolved in virtually all general systemic reactions of anorganism, including such important processes as theregulation of immune responses, inflammatory pro-cesses, and wound healing. Cytokines are importantmediators involved in embryogenesis and organ devel-opment and their activities in these processes may differfrom those observed postnatally. In addition, they playa key role in neuroimmunological, neuroendocrinologi-cal, and neuroregulatory processes. Furthermore, cyto-kines are important positive or negative regulators ofmitosis, differentiation, migration, cell survival/death,and transformation. On the immunological arena, it hasalso been shown that a number of viral infectious agentsexploit the cytokine repertoire of organisms to evadeimmune responses of the host. Virus-encoded factorsappear to affect the activities of cytokines in at least fourdifferent ways: (i) by inhibiting the synthesis and releaseof cytokines from infected cells, (ii) by interfering withthe interaction between cytokines and their receptors,(iii) by inhibiting signal transmission pathways of cyto-kines and (iv) by synthesizing virus-encoded cytokinesthat antagonize the effects of host cytokines mediatingantiviral processes. Bacteria and other microorganismsalso appear to produce cytokine-like substances thatthey use to subvert host responses [1–12].

Receptor-mediated regulation of cytokines

Cytokines themselves rarely are related closelyamong each other in terms of primary sequences. Someappear to have some common three-dimensional fea-tures and some of them can be grouped into families.For example, the TNF ligand superfamily members(with the exception of LT-a) are type II membraneglycoproteins with homology to TNF in the extracellu-lar domain [1–12]. The analysis of crystal structures ofseveral cytokines with very little sequence homology hasrevealed a common overall topology that is not deduc-ible from sequence comparisons. The biological activi-ties of cytokines are mediated by specific membranereceptors that can be expressed on virtually all cell typesknown [55–75]. Their expression is also subject to sev-eral regulatory mechanisms, although some receptorsare expressed also constitutively. Cytokine receptorproteins have been shown to share a number of char-acteristics and many receptors are members of cytokinereceptor families (Fig. 6). Many receptors, moreover,are multi-subunit structures that bind ligands and at thesame time possess functions as signal transducers due totheir intrinsic tyrosine kinase activity. Many receptorsoften share common signal transducing receptor com-ponents in the same family, which explains, at least inpart, the functional redundancy of cytokines. This and


the ubiquitous cellular distribution of certain cytokinereceptors have hampered attempts to define critical re-sponsive cell populations and the physiologically im-portant cell-specific functions of cytokines in vivo.Many receptors, furthermore, are associated with spe-cial signal transducing proteins in the interior of the celland some receptors may bind more than one cytokine.Several cytokine receptors have been shown to be con-verted into soluble binding proteins that regulate ligandaccess to the cell by specific proteolytic cleavage of re-ceptor ecto-domains [1–12].

Following the cloning of a plethora of mammalianand non-mammalian cytokine receptors, notable aminoacid homologies and conservation of characteristic se-quence motifs have allowed these receptors to be groupedinto a gene family and subfamilies (Table 2). Based ondetails of their structural organization, one generallydistinguishes between type-1 cytokine receptor family(class-1 cytokine receptor family) and type-2 cytokinereceptor family (class-2 cytokine receptor family). Thefamily of type-1 cytokine receptors includes those for IL-2 (b-subunit), IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11,

IL-12, EPO, GM-CSF, G-CSF, LIF, CNTF, and alsothe receptors for thrombopoietin (TPO), growth hor-mone, and prolactin. Further members of this proteinfamily are some commonly shared signal transducingcomponents such as gp130 and the c chain of the IL-2receptor. Upon binding of a ligand to the extracellulardomain of the type-1 receptors, the receptor moleculesform homodimers or heterodimers (in a few cases alsotrimers) and the intracellular receptor domains becomeassociated with a variety of signaling molecules, in par-ticular cytoplasmic tyrosine kinases and latent cytoplas-mic transcriptional activators. The conservedextracellular domain of these receptors has a length ofapproximately 200 amino acids (type-1 family domain),which contains four positionally conserved cysteine res-idues in the amino-terminal region and a Trp-Ser-X-Trp-Ser (WSXWS) motif located proximal to the transmem-brane domain [72,73]. The four cysteines appear to becritical to the maintenance of the structural and func-tional integrity of the receptors. The WSXWS consensussequence is thought to serve as a recognition site forfunctional protein–protein interaction of cytokine re-

Fig. 7. IL-1 and IL-6 cross-talk receptor signaling pathways.


ceptors. Peptides encompassed within the WSXWS re-gion have been shown to inhibit the priming effect of IL-3, IL-5, and GM-CSF on the synthesis of leukotriene C4induced by chemotactic peptides in a basophile mediatorrelease assay. Mutational analysis of the EPO receptorwithin the WSXWS motif indicates that it is critical forprotein folding, ligand binding, and signal transduction.Degenerate oligonucleotides to the common WSXWSmotif have been used to clone various forms of cytokinereceptors from cDNA libraries. Particularly, the notablefeature of the intracellular domain of type-1 receptors isthe absence of an intrinsic activity of a protein tyrosinekinase found in many other receptors. Furthermore, thecytoplasmic domains of the family members are less wellconserved, but some sequence similarities have been re-ported. The differential expression of receptor compo-nents and signaling molecules and the selectiverecruitment of different intracellular signaling compo-nents explains, at least in part, some of the overlappingbiological activities of the corresponding cytokine li-

gands. Sharing of different receptor components has beenused also to further subdivide the type-1 receptor familyfurther into three different subgroups according to thecritical signal transduction component used. Members ofthe family of type-2 cytokine receptors are only distantlyrelated to members of the type-1 receptors. The type-2receptor family includes receptors for IFN-a, IFN-b,IFN-c, IL-10, and tissue factor (coagulation factor-3).Type-2 receptors are multimeric receptors composed ofheterologous subunits. The extracellular domains sharestructural similarities in their ligand-binding domain.Several conserved intracellular motifs have been de-scribed and these probably function as binding sites forthe intracellular effector proteins Janus kinases andSTAT proteins. According to the nomenclature, the li-gand-binding subunit of a receptor is referred to as the achain. Other signal transducing subunits are named bchains or c chains. A subgroup of the cytokine receptorsuperfamily, called hematopoietin receptor superfamily,comprises receptors for IL-4, IL-6, IL-7, EPO, GM-CSF,

Fig. 8. TNF receptor signaling pathways.


prolactin, growth hormone, and the b subunit of the IL-2receptor [1–12,74–80]. Most of the receptors for solublefactors functioning in the hematopoietic system belongto the type-1 cytokine receptor family. Many of the cy-tokine receptors exist in membrane-bound and solubleforms. The soluble receptor forms may arise by proteo-lytic cleavage of transmembrane receptors or by usingalternatively spliced receptor mRNAs. They may act asinhibitors of cytokine activities or in a retrocrine fashion[80–86]. Schematic receptor signaling pathways mediatedby IL-1, IL-6, and TNF are shown in Figs. 7 and 8, re-spectively.

Conclusions and future prospects

The many specific, overlapping, and redundant activ-ities of individual cytokines have been the basis for cur-rent concepts of therapeutical intervention, in particularof the treatment of hematopoietic malfunctions and tu-mor therapy [1–5,75–88]. Applications involve the sup-port of chemo- and radiotherapy, bone marrowtransplantation, and general immuno-stimulation. Al-though some recombinant cytokines are now in clinicaluse and attempts are made to develop hybrid moleculesfrom known cytokines, which possess the advantages ofthe respective factors, but not their disadvantages, onemust be aware of the fact that current knowledge is stillprecarious. Cytokines are powerful two-edged weaponsthat can trigger a cascade of reactions and may show ac-tivities that often go beyond the single highly specificproperty that it is hoped they possess. New factors arebeing discovered constantly and they extend our knowl-edge about the cytokine network [7,12,20,87–92]. Never-theless, it can be stated that our new, yet growing,understanding of the biological mechanisms governingcytokine actions is an important contribution to medicalknowledge. The biochemistry and molecular biology ofcytokine actions explain some well known and sometimesalso some of the more obscure clinical aspects of diseases[93–99]. Knowledge that cytokines create regulatory hi-erarchies and provide independent and/or interrelatedregulatory mechanisms that can confer distinct and in-teractive developmental functions lays a solid, albeit ra-ther complicated foundation, for current and futureclinical applications.

Acknowledgments

The author�s own publications are, in part, financially supported bythe Anonymous Trust (Scotland), the National Institute for Biological

Standards and Control (England), the Tenovus Trust (Scotland), the

UK Medical Research Council (MRC, London), and the Wellcome

Trust (London). Dr. John J. Haddad holds the Georges John Livanos

prize (London) and the NIH award fellowship (UCSF, California,

USA).

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Cytokines and related receptor-mediated signaling pathwaysInflammatory cytokines as putative regulators of a plethora of cellular functionsThe evolution of the inflammatory process: an overviewThe nomenclature, nature, and biochemistry of cytokines: general aspects

The biology and pharmacology of cytokinesReceptor-mediated regulation of cytokinesConclusions and future prospectsAcknowledgementsReferences

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