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‫‪http://www.copewithcytokines.de/‬‬
‫مقدمه و کلیات‬
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.
‫گیرنده(پذیرنده) سایتوکاین ها‬
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
‫انواع سایتوکاینها‬
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 cell–derived 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. [email protected]
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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‫*‪ -‬عامل نکروزتومور (سایتوکاین های پیش التهابی)‬
‫*‪ -‬اینترفرونها‬
‫*‪-‬عوامل موثردرخونسازی‬
2.1 CD4+ T Cell and CD8+ T Cell
Thymus
Tc1
30%
Tc2
CD8
Th1
T
CD4
Th2
60%
Th3
Peripheral T
lymphocyte
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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‫*‪ -‬اینترفرونها‬
‫*‪-‬عوامل موثردرخونسازی‬
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‫کاربرد درمانی سایتوکاین ها‬
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.