Cytokines & Their Actions

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Presented byMr. SharanabasappaIst M.Pharm.Dept. of Pharmacology

Subject In ChargeDr. THIPPESWAMY B. S.

M.Pharm., Ph.DProfessor & Head of the DepartmentDEPT. OF PHARMACOLOGYSSCP, TUMKUR.

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Introduction

Definition

Cytokine categories

General characteristicsFunctional classes of cytokines

Chemokines

Therapeutic uses of cytokinesCommercial products of cytokines

References

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Cytokines (Greek cyto-, cell; and -kinos,

movement) are small cell-signaling protein molecules that are secreted

by the glial cells of the nervous system and by

numerous cells of the immune system and are acategory of signaling molecules used

extensively in intercellular communication.

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Low molecular weight soluble proteins(polypeptides) produced in response tomicrobes and other antigens.OR

Soluble mediators or glycoproteins that aid in thecommunication between cells, primary cells ofimmunological, haematological & neurologicalsystems.

NOTE :- Defining cytokines based only on theirproducer cells or target cells is inaccurate,because one producer cell one target cellhas been falsified for almost every cytokine.

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About 50 cytokines are identified which aregrouped in 6 categories.1) Interferons2) Interleukins

3) Tumour Necrosis Factor (TNF, Cachectin)4) Transforming Growth Factor (TGF)5) Colony Stimulating Factor (CSF)6) Growth Factors (PDGF, EGF, FGF, VEGF)

Cytokines involved in leucocyte endothelial cellinteraction are called Chemokines. Growthfactors & other cytokines are named

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Mediate and regulate the immune system

Secretion is brief and self-limited

Individual cytokines are produced by

multiple cell types

Act on multiple cell types-pleiotropic

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Cytokine actions may be characterized as:

Autocrine (self modulating)

Paracrine (modulating cells in theimmediate surroundings)

Endocrine (modulating cells throughcirculation in the distant area)

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Cytokines classified according to their biologicactions into three groups:

1) Mediators and regulators of innate immunity

- Produced by activated macrophages and NKcells in response to microbial infection

- they act mainly on endothelial cells andleukocytes to stimulate the early

inflammatory response to microbes

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2) Mediators and regulators of acquired immunity

- Produced mainly by T lymphocytes in response tospecific recognition of foreign antigens

- They include IL-2, IL-4, IL-5,, IL-13, IFN,

Transforming growth factor-(TGF-) andlymphotoxin (TNF- )

3) Stimulators of haematopoiesis

- Produced by bone marrow, stormal cells,leukocytes- Stimulate growth and differentiation ofleukocytes- Stem cell factor, IL-3, IL-7, GM-CSF

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*Interferons (IFNs): are proteins secreted inresponse to viral infections or other stimuli

* They include:

- INF- produced by leucocytesinduced by virus infected cells

- INF- produced by fibroblasts

- INF- produced by NK cells,TH1 cells, CD8 T-cells

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Action of INF- and IFN- :- Prevent viral replication

- Increase MHC-I expression on viralinfected cells helping their recognition byCD8 T-cells

- Increase cytotoxic action of Nk cells

- Inhibit cell proliferation and tumor growth16SSCP, TUMKUR


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Action of IFN- :

- Activate Macrophages

- Increase expression of MHC-I and II onAPCs

- Enhance cytotoxic actions of Nk cells

- Promote production of TH1 and inhibitsproliferation of TH2

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Group of cytokines (secreted proteins/signalingmolecules) that were first seen to beexpressed by white blood cells (leukocytes).

The function of the immune system depends ina large part on interleukins. The majority ofinterleukins are synthesized by helper CD4+ Tlymphocytes, as well as through monocytes,

macrophages, and endothelial cells.

They promote the development anddifferentiation of T, B, and hematopoietic cells.

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Interleukin Primary Cell Structure Primary ActivitiesIL 1/IL-1 Macrophages, NK

Cells, B cells

Inflammation

IL-2 T cells Activates T cells

IL-3 T cells Haematopoieticgrowth factor

IL-4 T cells B cell growth

IL-5 T cells Eosinophil & B cell

growth

IL-6 T cell & fibroblasts Inflammation

IL-7 Stromal cells B & T cell growth

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Interleukin Primary Cell Structure Primary Activities

IL-8 Macrophages Chemoattractant for

neutrophils

IL-9 Activated T cells T cell growth &

Potentiates IgM, IgG &

Ig EIL-10 B cells, T cells B cell growth /

inhibition of cytokinesynthesis by T cells

IL-11 Bone marrow stromal

cells

Haematopoietic co-

factor

IL-12 Macrophages, B cells Induction of cell

mediated immunity

IL-13 T cells B cell growth

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Interleukin Primary Cell Structure Primary Activities

IL-14 Activated B cells controls the growth

and proliferation of Bcells, inhibits Ig

secretion

IL-15 Epithelial cells T cell & NK cell growth

IL-16 CD8+ T cells CD4+ T cell

chemoattractant

IL-17 CD4+ T cells Fibroblast stimulation

IL-18 Macrophages Induces production

of IFN, NK cellactivity

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Has been described by a variety ofdifferent names:

Lymphocyte Activating Factor (LAF),

Endogenous pyrogen, T cell replacing factor II &

B cell differentiation factor, as well as by

several other names.

IL-1 represents at least two distinctpolypeptides (IL-1 alpha & IL-1 beta).

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The MWs of the polypeptides areapproximately 17 kDa.

IL-1 has been associated with numerousactivities. Some of these include

1. Induction of the IL-2 receptor;2. Stimulation of pre-B cell differentiation;

3. Augmentation of NK-cell cytotoxicity;

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4. Induction of adhesion molecules onendothelial cells;

5. Induction of fever;

6. Stimulation of thymocyte proliferation;

7. Enhancement of collagen production;

8. Stimulation of the release of other cytokinesinvolved in haematopoiesis.

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Originally described as T cell growth factor(TCGF).

Synthesized & secreted primarily by T cells.

Stimulate the growth, differentiation &

activation of T cells, B cells, & NK cells.

Produces its immunological effects by bindingto the cellular IL-2 receptor (IL-2R).

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Haematopoietic growth factor.

Principle effects are on early haematopoieticprogenitors in which Il-3 induces haematopoiesis

& cell differentiation.

Administration of IL-3 produces an increase inerythrocytes, neutrophils, eosinophils,

monocytes & platelets.

Act synergistically or additively with otherhaematopoietic growth factors.

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Primarily derived from T cells & principlesite of action is the B cell.

Stimulates B cell proliferation & activation.

Induces IgG1 & IgE expression from B cells& class II MHC expression.

Also induces the differentiation ofeosinophils & activity of T cytotoxic cells.

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Represents the compounds originallyknown as T cell replacement factor (TRF),eosinophil differentiation factor (EDF) &

B cell growth factor (BCGFII).

Primary effect is on the eosinophiliclineage.

Stimulates eosinophil chemotaxis &eosinophil expansion.

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Produced by lymphoid & non-lymphoidcells.

Acts on T cells & B cells.

Stimulates multilineage haematopoiesis,including the maturation of

megakaryocytes.

Formerly known as interferon-2 for itsweak antiviral activity.

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Acts primarily on pre-B cells to stimulatetheir differentiation.

Also stimulate the development of humanT cells.

Overall, it appears that IL-7 is importantin B & T cell development.

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Member of a group of glycoproteins knownas Chemokines.

Potent chemoattractant for neutrophils.

Has a wide variety of pro-inflammatoryeffects, including the stimulation of

neutrophil degranulation & enhancement ofneutrophil adherence to endothelial cells.

IL-8 is the lowest MW IL only 8 kDa.

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Group of cytokines which can cause cell death(Apoptosis).

Family members :- 19 cytokines are identifiedas part of the TNF family on the basis ofsequence, functional & structure similarities.

The first two members of the family to beidentified were; TNF- TNF-

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Monocyte derived cytotoxin; implicated intumor regression, septic shock & cachexia.

Stimulate cell proliferation & induce celldifferentiation under certain conditions.

Potent pyrogen, causing fever by directaction or by stimulation of IL-1 secretion.

Cause cytolysis of certain tumor cell lines.

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Also know as lymphotoxin is a cytokinewhich is inhibited by IL-10.

Lymphotoxin & lymphotoxin , tworelated cytokines produced by

lymphocytes that are cytotoxic for a widerange of tumor cells in vitro & in vivo.

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Sometimes referred to as Tumor Growth Factor.

Two classes of polypeptide growth factors, TGF -

& TGF .

The two classes of TGFs are not structurally orgenetically related to one another & they actthrough different receptor mechanisms.

They dont always induce cellular transformation,and are not the only growth factors that inducecellular transformation.

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upregulated in some human cancers. It isproduced in macrophages, brain cells,

and keratinocytes, &induces epithelial development.

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Exists in three known subtypes in humans,TGF1, TGF2, and TGF3.

These are upregulated in Marfan'ssyndrome and some human cancers.

Play crucial roles in tissue regeneration,cell differentiation, embryonicdevelopment, and regulation of theimmune system.

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colony-stimulating factors are soluble,membrane-bound substances of

the hematopoietic microenvironment.

secreted glycoproteins that bind to

receptor proteins on the surfacesof hemopoietic stem cells.

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Thereby activating intracellular signalingpathways that can cause the cells

to proliferate and differentiate into aspecific kind of blood cell (usually whiteblood cells).

They may be synthesized & administeredexogenously.

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A protein secreted by macrophages, Tcells, mast cells ,endothelial cells,

and fibroblasts.

Functions as a WBC growth factor.

Stimulates stem cells to producegranulocytes & monocytes.

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A naturally occurring substance capable ofstimulating cellular growth, proliferation &cellular differentiation.

Usually it is a protein or a steroidhormone.

Growth factors are important forregulating a variety of cellular processes.

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Growth factors typically act as signalingmolecules between cells.

Ex :- Cytokines & hormones which bind to specificreceptors on the surface of their target cells.

They often promote cell differentiation andmaturation, which varies between growth factors.

Ex :- bone morphogenic proteins stimulate bone

cell differentiation, while fibroblast growthfactors & vascular endothelial growthfactors stimulate blood vessel differentiation(angiogenesis)

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Individual growth factor proteins tend tooccur as members of larger families ofstructurally & evolutionarily related proteins.

There are many families, like

Bone morphogenetic proteins (BMPs)

Epidermal growth factor (EGF)

Erythropoietin (EPO)

Thrombopoietin (TPO)

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Family of chemoattractants for inflammatory cells& include;

IL-8 chemotactic for neutrophils

Platelet factor 4 chemotactic for neutrophils,monocytes & eosinophils

MCP 1 chemotactic for monocytes

Eotaxin chemotactic for eosinophils

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Chemokines are a family of small (8 to 10kDa) proteins which act primarily as

chemoattractants for specific types ofleukocytes.

About 40 different chemokines & 20different receptors for chemokines areidentified.

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Classified into four major groups,according to the arrangement of the

conserved cysteine (C) residues in themature proteins.

1. C-X-C chemokines ( chemokines)

2. C-C chemokines( chemokines)3. C chemokines ( chemokines)

4. CX3C chemokines

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Have one amino acid residue separating the firsttwo conserved cysteine residues.

Act primarily on neutrophils.

IL-8 is typical of this group.

Secreted by activated macrophages, endothelial

cells, neutrophils, with limited activity onmonocytes & eosinophils.

Inducers are microbial products & other cytokines,mainly IL-1 & TNF.

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Have the first two conserved cysteine residuesadjacent.

Induces monocyte chemoattractant protein (MCP-

1), eotaxin, macrophage inflammatory protein - 1(MIP - 1) & RANTES ( regulated & normal T cellexpressed & secreted).

Attract monocytes, eosinophils, basophils &lymphocytes but not neutrophils.

Eotaxin selectively recruits eosinophils.

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Lack two (first & third) of the fourconserved cysteines.

C chemokines (lymphotactin) arerelatively specific for lymphocytes.

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Contain 3 amino acids between the twocysteines.

Only know member of this class is calledfractalkine, which exists in two forms.

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1) Interferon in treatment of viral diseases, cancer.

2) Several cytokines are used to enhance T-cell activationin immunofideficincy diseases, e.g. IL-2, IFN-K,TNF-E.

3) IL-2 and lymphokine activating killer cells (LAK) intreatment of cancer.

4) GM-CSF induces increase in white cell count, it is used:

a- To restore leukocytic count after cytotoxicchemotherapy induced neutropenia

b- After bon marrow transplantation

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5) Anti-cytokines antibodies in management ofautoimmune diseases and transplant rejection:

a- Anti-TNF in treatment rheumatoid arthritis

& Crohns disease.b- Anti-IL2R to reduce graft rejection

6) Anti-TNF antibodies in treating septic shock

7) Anti-IL-2R E in treating adult T-cell leukemia

8) Anti-IL-4 is under trial for treatment ofallergies

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ALDESLEUKIN

Recombinant human IL-2 (rIL-2), knowngenerically as aldesleukin, is available as

Proleukin.

Chemical name :- des-alanyl-I, serine-125-humaninterleukin-2.

First approved indication was in 1992 for thetreatment of metastatic renal cell carcinoma.

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OPRELVEKIN Recombinant human IL-11, available as the

product Neumega.

Indicated for the prevention of severethrombocytopenia.

Mechanism stimulation & proliferation ofboth haematopoietic stem cells &megakaryocyte progenitor cells, & theinduction of megakaryocyte maturation.

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OTHERS

IL-3 (muplestim) support of haematopoiesisafter high-dose chemotherapy or bone marrowfailure, & for myelodysplastic syndromes.

IL-6 (sigosix) potential platelet stimulator

TNF inhibitors Etanercept, Infliximab etc

IL-1 antagonist Anakinra

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Pathological Basis of Disease. Robbins &Cotran; 7th edition: Pg no. 71-72.

Pharmaceutical Biotechnology. J. A.Crommelin & Robert D Sindelar; 2nd

edition: Pg no. 217 to 230.

Text book of Pathology. Harsh Mohan;5th edition: Pg no. 31-32, 143.

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Pharmacology. H. P. Rang, M. M. Dale, J. M.Ritter & P. K. Moore; 5th edition: Pg no.239-40.

Essential of medical pharmacology. K. D.Tripathi; 6th edition: Pg no. 204-05.

http://en.wikipedia.org/wiki/Cytokine

http://www.cytokines.com/SSCP, TUMKUR 58


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Cytokines & Their Actions