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: /http://www.copewithcytokines.de

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 locally

Differ from growth factors that are produced constitutively, while cytokine production is carefully regulated

Cytokine nomenclature
Interleukins (1-35) Interferons (a,b,...,- g)

TNF superfamily
Chemokines Others

Properties of cytokines
Proteins Low molecular weight Bind to receptor on either cell which produced it or another cell Receptor binding triggers a signal Signal results in altered pattern of gene expression

Cytokine -mediated effects

Cell growth Cell differentiation Cell death Induce non-responsiveness to other cytokines/cells Induce responsiveness to other cytokines/cells Induce secretion of other cytokines

Cytokines can act in three different manners

Autocrine
Cytokine binds to receptor on cell that secreted it

Paracrine
Cytokine binds to receptors on near by cells

Endocrine
Cytokine binds cells in distant parts of the body

Cytokine Actions
Pleiotropy
Act on more than one cell type (INFa/b)

Redundancy
More than one cytokine can do the same thing (IFNa/b and IFNg)

Synergy
Two 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-12 and IL-8)

Antagonism
Two or more cytokines work against each other (IL-4 and IL-12)

How can non-specific cytokines act specifically?

Only cells expressing receptors for specific cytokines can be activated by them Many 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

Control of cytokine function 1. DNA level

cytokine genes are normally switched off (ie. inducible)
except for a few where the products require steady state synthesis eg M- CSF, G-CSF, SCF, IL-6, Epo.

Control of cytokine function 2. post-transcriptional

mRNA instability There are repeats of a common consensus octamer at the 3 untranslated end of the mRNA which confers instability -UUAUUUAU-

Control of cytokine function 3. 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-promoting and growth-inhibitory actions. eg. TNF alpha/TGF beta, any CSF/IFN alpha/beta, EGF/TGF alpha IL-4 / IFN gamma - Th1 and Th2-type T lymphocyte responses eg. CMI or IgE

Control of cytokine function 4. responding cell

up- and down-regulation of receptors induction or amplification of inflammation ie. by pro-inflammatory cytokines eg TNF induces IL-1, and IL-1 induces IL-6. feedback inhibition. Il-1 induces PGE2 which upregulates adenylate cyclase which increases the intracellular cAMP and down-regulates the production of IL-1 and IL-2. Cortisol is stimulated as part of the stress response and this directly down-regulates IL-1 and IL-2.

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Cytokine receptor families

Immunoglobulin 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 family Toll-like receptor family (IL-1) Chemokine receptor family (GPCR)

http://www.nature.com/nri/journ al/v1/n3/animation/nri1201200a_swf_MEDIA1.html

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 have the same activity as the native purified molecule.

IL-1 can be produced by all nucleated cells, has a wide

range of biological activities on many target cell types. In vivo it induces hypotension, fever, weight loss, neutropoenia and acute phase response. Main function is as a dendritic cell-derived factor which specifically promotes the proliferation of T lymphocytes.

Interleukins (2)
IL-2 is a T-cell-derived cytokine which was

first described as a T cell growth factor. Now known to stimulate growth and differentiation of T, B, NK cells, monocytes, macrophages and oligodendrocytes.

IL-3 is a haematopoetic growth factor which

stimulates colony formation of erythroid, megakaryocyte, neutrophil, eosinophil, basophil, mast cell and monocyte lineages.

Interleukins (3)
IL-4 from T-cells and mast cells and acts on B-cells,

T-cells, endothelial cells and fibroblasts. It induces the secretion of IgE and IgG4 by B-cells. It shares this property with IL-13. IL-5 is a T-cell derived glycoprotein which stimulates eosinophil colony formation and is an eosinophil differentiation factor. IL-6 is multifunctional, secreted by lymphoid and nonlymphoid cells. It regulates B-cell function, haematopoesis and the acute phase response.

Interleukins (4)
IL-7 is a stromal-cell derived factor for progenitor B-cells

and T-cells. The main lymphocyte population in the thymus responsive to IL-7 is CD4-ve/CD8-ve. IL-7 also promotes growth and differentiation of mature T-cells. IL-8 is an inflammatory cytokine, produced by many cell types, which functions as a neutrophil chemo-attractant and activation factor. It also attracts basophils and a subpopulation of lymphocytes. It is a potent angiogenic factor. IL-9 enhances the proliferation of T-lymphocytes, mast cell lines and erythroid precursors.

Interleukins (5)
IL-10 is secreted by TH0 and TH2 subsets of CD4

lymphocytes. It blocks activation of cytokine synthesis by TH1 lymphocytes, activated monocytes and NK cells. It stimulates or enhances the proliferation of B-cells, thymocytes and mast cells and it co-operates with TGF beta to stimulate IgA production by human B-cells. There is a high degree of homology between IL-10 and an open reading frame (BCRF1) in the EBV genome. The protein encoded has some of the activities of IL-10 and has been designated vIL10. IL-11 is a growth factor for plasmacytoma and macrophage progenitors. It is related to IL-6.

Interleukins (6)
IL-12 is important against intracellular pathogens. It

induces IFN gamma production by T-cells and NK cells, and enhances NK and ADCC activity. It stimulates the proliferation and differentiation of the TH1 CD4 subset. IL-13 is secreted by activated T-cells and inhibits the production of inflammatory cytokines eg (IL-1b, IL-6, TNFa, IL-8) by LPS-activated monocytes. It induces CD23 expression on B cells, and with anti-Ig or anti-CD40 can stimulate the secretion of IgM, IgE, and IgG4. IL-14 enhances the proliferation of activated B-cells. and inhibits Ig synthesis.

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 the production of inflammatory mediators (GM-CSF, IL-1beta and TNF alpha) by synoviocytes in arthritis, and macrophages. IL-18 produced by activated macrophages. Can induce Th2type cytokines alone or can induce IFN-gamma production and promotes Th1-type immune responses in synergy with IL-12.

Interleukins (8)
IL-19 IL-10 family member, no function ascribed
IL-20 IL-10 family member, regulates participation of

keratinocytes 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 dendritic cells, stimulates IFN and T memory cell proliferation, transgenics have multiple organ inflammation, IL-24 IL-10 family member, binds keratinocytes.

IL-25
Interleukin-25 is a novel cytokine

involved in Th1/Th2 regulation which promotes Th2 responses by inducing cytokines such as IL-4, IL-5 and IL-13

IL-26
cytokine of the IL-10 family

 IL27 acts in synergy with IL12

IL27 triggers expansion of antigen-

specific naive CD4-positive T cells and promotes polarization towards a Th1 phenotype with expression of gammainterferon

IL-28 , IL-29
Interleukin 28 and Interleukin 29 May

Have Therapeutic Value Against Hepatitis Viruses in Humans Interleukin 28 and interleukin 29 (IL-28 and IL-29) are a recently discovered family of novel class II cytokines distantly related to interferon alpha and interleukin 10 (IL-10).

IL-30
This is the new name of P28 , a subunit

of IL27

IL-31
T cellderived cytokines are important in the development

of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL31 developed severe pruritis, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.

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. soohyun.kim@uchsc.edu

IL-33, an interleukin-1-like cytokine

IL-33, an interleukin-1-like cytokine that signals via

the IL-1 receptor-related protein ST2 and induces T helper 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 California Avenue, 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 to treat 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-1 receptor is ST 2. This receptor has been described as a negative regulator of Tolllike receptor-IL-1 receptor signaling, but it also functions as an important effector molecule of T helper type 2 responses. We report a member of the IL-1 family, IL33, which mediates its biological effects via IL-1 receptor ST 2, activates NFkappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL5, and IL-13 and leads to severe pathological changes in mucosal organs.

Interleukin-34
Regulation of Myeloid Growth and

Differentiation by a Novel Cytokine, Interleukin-34 (IL-34), via the CSF-1 Receptor

IL-35
Nature 450, 566-569 (22 November 2007)

The inhibitory cytokine IL-35 contributes to regulatory Tcell function.

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

IL-35 is a novel cytokine with therapeutic effects against collagen-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

Thymus

Tc1 30% Tc2

CD8 Th1

T
Peripheral T lymphocyte

CD4

Th2

60%
Th3

CD4+ 25+

Tr1

Treg

5-10%

Nature Immunology 6, 1069 - 1070 (2005) TH-17: a giant step from TH1 and TH2

2.1 CD4+ T Cell

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 20

2.1 CD4+ T Cell

Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties

Diversification of CD4 T Cell Lineages

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Clinical applications
Recombinant cytokines (mAbs) enough safety Which diseases auto-immune disease infectious diseases immuno-deficiencies malignancy

Clinical Use of Cytokines

Interferons a (Roferon, Alferon-N, Intron A) antiviral therapy (chronic Hepatatis B and C), hairy cell leukemia. Interferon b (Betaseron) multiple sclerosis. G-CSF (Neupogen) supportive treatment for bone marrow transplantation. Interferon g (Actimunne) chronic granulomatosis. Epo (Procrite) kidney disorders. GM-CSF, IFN-g, IL2, TNF all toxic when applied systemically.