Introduction to cytokines
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Transcript Introduction to cytokines
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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.
انواع دیگر سایتوکاین ها:
* -عامل نکروز تومور (سایتوکاین های پیش التهابی)
* -اینتر فرونها
*-عوامل موثر در خونسازی
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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* -اینتر فرونها
*-عوامل موثر در خونسازی
کمو کاین ها
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.