cytokine class

8/3/2019 Cytokine Class

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http://www.copewithcytokines.de/
http://www.copewithcytokines.de/http://www.copewithcytokines.de/


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What are cytokines?

A group of proteins used for communications

between cells

Play role similar to hormones (messengers of the

endocrine system)

Hormones usually act at a distance

Cytokines act locallyDiffer from growth factors that are produced

constitutively, while cytokine production is

carefully regulated


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Cytokine nomenclature

Interleukins (1-35)

Interferons (a,b,...,- g)

TNF superfamily

Chemokines

Others


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Properties of cytokines

Proteins

Low molecular weight

Bind to receptor on either cell which producedit or another cell

Receptor binding triggers a signal

Signal results in altered pattern of geneexpression


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Cytokine -mediated effectsCell growth

Cell differentiation

Cell deathInduce non-responsiveness to othercytokines/cells

Induce responsiveness to othercytokines/cells

Induce secretion of other cytokines


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Cytokines can act in threedifferent manners

Autocrine

Cytokine binds to receptor on cell that

secreted it

Paracrine

Cytokine binds to receptors on near by cells

EndocrineCytokine binds cells in distant parts of the

body


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Cytokine Actions

PleiotropyAct on more than one cell type (INFa/b)

Redundancy

More than one cytokine can do the same thing (IFNa/band IFNg)

SynergyTwo or more cytokines cooperate to produce an effect

that is different or greater than the combined effect of

the two cytokines when functioning separately (IL-12and IL-8)

AntagonismTwo or more cytokines work against each other (IL-4

and IL-12)


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How can non-specific

cytokines act specifically?

Only cells expressing receptors for specific

cytokines can be activated by themMany cytokines have very short half-lives

Only cells in close proximity will be activated

High concentrations of cytokines are needed for

activation

Only cells in close proximity will be activated

May require cell-to cell contact


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Control of cytokine function1. DNA level

cytokine genes are normally switchedoff (ie. inducible)

except for a few where the products require

steady state synthesis eg M- CSF, G-CSF, SCF,

IL-6, Epo.


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Control of cytokine function2. post-transcriptional

mRNA instability There are repeats of a

common consensus octamer at the 3untranslated end of the mRNA which confersinstability -UUAUUUAU-


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Control of cytokine function3. post-secretion

Short half-life in serum eg. TNF = 15min

Soluble cytokine receptors, sTNF-R

IL-1 receptor antagonist (IL-1Ra)

cytokines with opposing actions, growth-promotingand growth-inhibitory actions. eg. TNF alpha/TGFbeta, any CSF/IFN alpha/beta, EGF/TGF alpha

IL-4 / IFN gamma - Th1 and Th2-type T

lymphocyte responses eg. CMI or IgE


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Control of cytokine function4. responding cell

up- and down-regulation of receptors

induction or amplification of inflammation ie. bypro-inflammatory cytokines

eg TNF induces IL-1, and IL-1 induces IL-6.

feedback inhibition. Il-1 induces PGE2 which up-regulates adenylate cyclase which increases theintracellular cAMP and down-regulates theproduction of IL-1 and IL-2. Cortisol is stimulated

as part of the stress response and this directlydown-regulates IL-1 and IL-2.


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(


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Cytokine receptor familiesImmunoglobulin superfamily receptors

Class I cytokine receptor family (hematopoietin

receptors)Binds most of the cytokines in the immune and

hematopoietin systems

Class II cytokine receptor family (IFN)

TNF receptor familyToll-like receptor family (IL-1)

Chemokine receptor family (GPCR)


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http://www.nature.com/nri/journ

al/v1/n3/animation/nri1201-

200a swf MEDIA1.html
http://www.nature.com/nri/journal/v1/n3/animation/nri1201-200a_swf_MEDIA1.htmlhttp://www.nature.com/nri/journal/v1/n3/animation/nri1201-200a_swf_MEDIA1.htmlhttp://www.nature.com/nri/journal/v1/n3/animation/nri1201-200a_swf_MEDIA1.htmlhttp://1.ppt/http://1.ppt/http://www.nature.com/nri/journal/v1/n3/animation/nri1201-200a_swf_MEDIA1.htmlhttp://www.nature.com/nri/journal/v1/n3/animation/nri1201-200a_swf_MEDIA1.htmlhttp://www.nature.com/nri/journal/v1/n3/animation/nri1201-200a_swf_MEDIA1.htmlhttp://www.nature.com/nri/journal/v1/n3/animation/nri1201-200a_swf_MEDIA1.html


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http://1.ppt/http://1.ppt/


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Interleukins(1)

This nomenclature started in 1979. For this designation

the gene sequence of the protein must be unique.

the protein will have also been cloned (cDNA)

the recombinant protein (eg, rIL-1) shown to havethe same activity as the native purified molecule.

IL-1 can be produced by all nucleated cells, has a widerange of biological activities on many target cell types.

In vivoit induces hypotension, fever, weight loss,neutropoenia and acute phase response.

Main function is as a dendritic cell-derived factor whichspecifically promotes the proliferation of T lymphocytes.
http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/


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Interleukins(2)

IL-2is a T-cell-derived cytokine which wasfirst described as a T cell growth factor.Now known to stimulate growth and

differentiation of T, B, NK cells, monocytes,macrophages and oligodendrocytes.

IL-3is a haematopoetic growth factor whichstimulates colony formation of erythroid,megakaryocyte, neutrophil, eosinophil,basophil, mast cell and monocyte lineages.
http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/


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Interleukins(3)

IL-4 from T-cells and mast cells and acts on B-cells,T-cells, endothelial cells and fibroblasts. It inducesthe secretion of IgE and IgG4 by B-cells. It sharesthis property with IL-13.

IL-5is a T-cell derived glycoprotein which stimulateseosinophil colony formation and is an eosinophildifferentiation factor.

IL-6 is multifunctional, secreted by lymphoid and non-

lymphoid cells. It regulates B-cell function,haematopoesis and the acute phase response.
http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/


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Interleukins(4)

IL-7 is a stromal-cell derived factor for progenitor B-cellsand T-cells. The main lymphocyte population in the thymusresponsive to IL-7 is CD4-ve/CD8-ve. IL-7 also promotesgrowth and differentiation of mature T-cells.

IL-8is an inflammatory cytokine, produced by many celltypes, which functions as a neutrophil chemo-attractant andactivation factor. It also attracts basophils and asubpopulation of lymphocytes. It is a potent angiogenicfactor.

IL-9 enhances the proliferation of T-lymphocytes, mast celllines and erythroid precursors.
http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/


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Interleukins(5)

IL-10is secreted by TH0 and TH2 subsets of CD4lymphocytes. It blocks activation of cytokine synthesis byTH1 lymphocytes, activated monocytes and NK cells. Itstimulates or enhances the proliferation of B-cells,thymocytes and mast cells and it co-operates with TGF betato stimulate IgA production by human B-cells. There is ahigh degree of homology between IL-10 and an open readingframe (BCRF1) in the EBV genome. The protein encoded hassome of the activities of IL-10 and has been designated vIL-

10. IL-11 is a growth factor for plasmacytoma and macrophage

progenitors. It is related to IL-6.


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Interleukins(6)

IL-12 is important against intracellular pathogens. Itinduces IFN gamma production by T-cells and NK cells, andenhances NK and ADCC activity. It stimulates theproliferation and differentiation of the TH1 CD4 subset.

IL-13 is secreted by activated T-cells and inhibits theproduction of inflammatory cytokines eg (IL-1b, IL-6, TNFa,IL-8) by LPS-activated monocytes. It induces CD23expression on B cells, and with anti-Ig or anti-CD40 canstimulate the secretion of IgM, IgE, and IgG4.

IL-14 enhances the proliferation of activated B-cells. andinhibits Ig synthesis.


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Interleukins(7)

IL-15 shares properties with IL-2.

IL-16 produced by fibroblasts and epithelial cells, chemo-attractant for CD4+ cells (T cells, macrophages, monocytes,eosinophils).

IL-17 produced by CD4+ lymphocytes and activates theproduction of inflammatory mediators (GM-CSF, IL-1betaand TNF alpha) by synoviocytes in arthritis, andmacrophages.

IL-18 produced by activated macrophages. Can induce Th2-type cytokines alone or can induce IFN-gamma productionand promotes Th1-type immune responses in synergy withIL-12.
http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/


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Interleukins(8)

IL-19 IL-10 family member, no function ascribed

IL-20IL-10 family member, regulates participation ofkeratinocytes in inflammation

IL-21 IL-10 family member IL-22 IL-10 family member, produced by activated T cells,

no inhibition of monokines

IL-23 similar to IL-12, produced by activated dendriticcells, stimulates IFN and T memory cell proliferation,

transgenics have multiple organ inflammation, IL-24 IL-10 family member, binds keratinocytes.
http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/


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IL-25

Interleukin-25 is a novel cytokine

involved in Th1/Th2 regulation whichpromotes Th2 responses by inducing

cytokines such as IL-4, IL-5 and IL-13
http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/


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IL-26

cytokine of the IL-10 family
http://1.ppt/http://1.ppt/http://1.ppt/


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IL27 acts in synergy with IL12

IL27 triggers expansion of antigen-

specific naive CD4-positive T cells andpromotes polarization towards a Th1phenotype with expression of gamma-interferon
http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/


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IL-28 , IL-29

Interleukin 28 and Interleukin 29 May

Have Therapeutic Value AgainstHepatitis Viruses in Humans

Interleukin 28 and interleukin 29 (IL-28and IL-29) are a recently discovered

family of novel class II cytokinesdistantly related to interferon alphaand interleukin 10 (IL-10).
http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/http://1.ppt/


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IL-30

This is the new name of P28 , a subunitof IL27
http://1.ppt/http://1.ppt/http://1.ppt/http://www.copewithcytokines.de/cope.cgi?007405http://www.copewithcytokines.de/cope.cgi?005169http://www.copewithcytokines.de/cope.cgi?005169http://www.copewithcytokines.de/cope.cgi?005169http://www.copewithcytokines.de/cope.cgi?007405http://www.copewithcytokines.de/cope.cgi?007405


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IL-31

T cellderived cytokines are important in the developmentof an effective immune response, but when dysregulatedthey can promote disease. Here we identify a four-helixbundle cytokine we have called interleukin 31 (IL-31), whichis preferentially produced by T helper type 2 cells. IL-31

signals through a receptor composed of IL-31 receptor Aand oncostatin M receptor. Expression of IL-31 receptor Aand oncostatin M receptor mRNA was induced in activatedmonocytes, whereas epithelial cells expressed bothmRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritis, alopecia and skin lesions.Furthermore, IL-31 receptor expression was increased indiseased tissues derived from an animal model of airwayhypersensitivity. These data indicate that IL-31 may beinvolved in promoting the dermatitis and epithelialresponses that characterize allergic and non-allergicdiseases.


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1: Immunity. 2005 Jan;22(1):131-42. Related Articles,Links

Interleukin-32: a cytokine and inducer of TNFalpha.

Kim SH, Han SY, Azam T, Yoon DY, Dinarello CA.

Department of Medicine, University of Colorado Health Sciences Center,Denver, CO 80262, USA. [email protected]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15664165&tool=ExternalSearchhttp://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=3533&uid=15664165&db=PubMed&url=http://www.facultyof1000.com/article/15664165http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=3048&uid=15664165&db=PubMed&url=http://linkinghub.elsevier.com/retrieve/pii/S1074761304003802http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15664165&tool=ExternalSearch


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IL-33, an interleukin-1-like cytokine

IL-33, an interleukin-1-like cytokine that signals viathe IL-1 receptor-related protein ST2 and induces Thelper type 2-associated cytokines.

Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK,Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA.

Schering-Plough Biopharma (formerly DNAX Research, Inc.), 901 CaliforniaAvenue, Palo Alto, California 94304, USA.

Cytokines of the interleukin-1 (IL-1) family, such as IL-1 alpha/beta and IL-18,have important functions in host defense, immune regulation, and inflammation.Insight into their biological functions has led to novel therapeutic approaches totreat human inflammatory diseases. Within the IL-1 family, IL-1 alpha/beta, IL-1Ra,and IL-18 have been matched to their respective receptor complexes and have

been shown to have distinct biological functions. The most prominent orphan IL-1receptor is ST 2. This receptor has been described as a negative regulator of Toll-like receptor-IL-1 receptor signaling, but it also functions as an important effectormolecule of T helper type 2 responses. We report a member of the IL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokinesfrom in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Schmitz+J%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Owyang+A%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Oldham+E%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Song+Y%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Murphy+E%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22McClanahan+TK%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Zurawski+G%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Moshrefi+M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Qin+J%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Li+X%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Gorman+DM%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Bazan+JF%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Kastelein+RA%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Kastelein+RA%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Bazan+JF%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Gorman+DM%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Li+X%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Qin+J%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Moshrefi+M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Zurawski+G%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22McClanahan+TK%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Murphy+E%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Song+Y%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Oldham+E%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Owyang+A%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Schmitz+J%22%5BAuthor%5D


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Interleukin-34

Regulation of Myeloid Growth andDifferentiation by a Novel Cytokine,

Interleukin-34 (IL-34), via the CSF-1Receptor


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IL-35

Nature450, 566-569 (22 November 2007)

The inhibitory cytokine IL-35 contributes to regulatory T-cell function.

Eur J Immunol. 2007 Nov;37(11):3021-9

IL-35 is a novel cytokine with therapeutic effects againstcollagen-induced arthritis through the expansion of

regulatory T cells and suppression of Th17 cells.


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2.1 CD4+ T Cell and CD8+ T Cell


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T

CD8

CD4

CD4+

25+

Th1

Tc2

Tc1

Th2

Th3

Tr1Peripheral Tlymphocyte

5-10%

30%

60%

Thymus

Treg

Nature Immunology 6 1069 - 1070 (2005)2.1 CD4+ T Cell


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Nature Immunology6, 1069 - 1070 (2005)TH-17: a giant step from TH1 and TH2

Development of IL-17-producing effector CD4+ T cells (TH-17)by IL-23 is inhibited by IFN- and IL-4.

Immunity 9/3/2006 Top 202.1 CD4+ T Cell


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Th17: An Effector CD4 T Cell Lineagewith Regulatory T Cell Ties

Diversification of CD4 T Cell Lineages

Immunity9/3/2006 Top 20


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Clinical applications

Recombinant cytokines (mAbs)

enough

safety -

Which diseases

auto-immune disease

infectious diseases immuno-deficiencies

malignancy

Clinical Use of


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Interferons a(Roferon, Alferon-N, Intron A) antiviral therapy (chronic Hepatatis B and C), hairycell leukemia.

Interferon b(Betaseron) multiple sclerosis.

G-CSF (Neupogen) supportive treatment for bonemarrow transplantation.

Interferon g(Actimunne) chronic granulomatosis.

Epo (Procrite) kidney disorders.GM-CSF, IFN-g, IL2, TNF all toxic when appliedsystemically.

Clinical Use ofCytokines


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cytokine class

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