Transcript Cytokines and Chemokines

Medical Immunology
Cytokines，CKs
陈建忠
浙江大学免疫学研究所
Cytokines
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Concept
Characteristics
Classification
Cytokine receptor
Biologic activity
Introduction to cytokines
• Cytokines (CKs)
Cytokines are small proteins that
are secreted by cells and exert their
biological activity through specific
cell surface receptors.
Introduction to cytokine
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Nomenclature
Old：monokine,lymphokine,
New：colony stimulating factor,
interleukin, interferon, tumor necrosis
factor,growth factor, chemokine
Introduction to CKs
• General properties of CKs
1.Small proteins (MW:approx. 15-30 KD);
2.Extremely potent, acting at pM or fM
3.The production is transient and tightly
regulated;
4.Autocrine , paracrine or endocrine;
5.Non-specific and non-MHC restriction；
Introduction to CKs
• Cytokine Actions
• Pleiotropy:Act on more than one
cell type (IFN-α / β)
• Redundancy:More than one
cytokine have the same action
(IFN- α / β and IFN- γ)
Introduction to CKs
• Cytokine Actions
• Synergy:Two or more CKs 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-18)
• Antagonism:Two or more cytokines
work against each other (IL-4 and IL-12)
Introduction to cytokine
• The CKs network
It has been shown above that there
are many CKs with multiple functions
and apparent redundancy of action
forming a complex communication
network.
Cytokines network
Categories of CKs
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Interleukin (IL)
Interferon (IFN)
Tumor necrosis factor (TNF)
Colony stimulating factor (CSF)
Chemokine
Growth factor(GF)
interleukin, IL
• IL 1～33
IL-2（T cell growth factor）
IL-4（ B cell growth factor ,Th2 type）
IL-6（ Th2 type ）
IL-8（belongs to chemokine）
IL-10（Th2 type）
IL-11（stimulator of platelet）
IL-12（Th2 type）
IL-2
interferon, IFN
• IFNs mediate the early innate
immune response;
• groups
type I IFN: IFN-α and IFN-β.
The major source is leukocyte,
fibroblasts and virus infected cells；
type II IFN : IFN-γ .
IFN-γ is mainly produced by
activated T cells and NK cells.
IFN-a
的 抗 病 毒 作 用
病毒
抑制病
毒复制
病毒复制
IFN-诱导蛋白
诱导刺激
信号转导
胞核
胞核
IFN-a
Tumor necrosis factor, TNF
• TNF: cause the necrosis of tumors
• TNF-αand TNF-β.
• TNF-α was produced by LPS-stimulated
mononuclear phagocytes and activted T
cells；
• TNF-β：also termed as lymphotoxin
( LT），and the major source is
activated T cells.
Colony-stimulating factor, CSF
• Stimulating the differentiation and
expansion of bone marrow
progenitor; be assayed by their
ability to stimulate the formation of
cell clonies in culture.
• Including IL-3, CSF(G-CSF, M-CSF,
GM-CSF), SCF, EPO, TPO, etc .
Chemokine
• Chemokines are a large family of
structurally homologous CKs that
stimulate movement and regulate
the migration of leukocytes from
the blood to tissues, including about
50 different chemokines.
• subfamiles: CXC, CC, C, CX3C, based
on structural characteristic
(cysteine residues).
Chemokine
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IL-8
MCP-1
Lymphotactin
Fractalkine
CXC
CC
C
CX3C
neutrophils
monocyte
lymphocyte
lymphocyte
Growth factor(GF)
• Promoting the proliferation and
differentiation of cells;
• Including TGF-、EGF、VEGF、FGF、
NGF、PDGF , etc.
cytokine receptor
1.Five families
• Ig superfamily receptors
• Class I cytokine receptor family
• Class Ⅱ cytokine receptor family
• Class Ⅲ cytokine receptor family
(TNF receptor family)
• Chemokine receptor family
CK receptor
• Multi-subunit receptor
one for cytokine binding
another for cytokine signaling
CK Receptor
• Common receptor subunit
There is same receptor subunit for
cytokine signaling among the
different cytokine receptors. e.g. IL2Rγ
CK Receptor
CK Receptors
• Soluble cytokine receptors
Functions：
①antagonist of CKs；
②delivery tools of CKs；
③as a index of diagnosis and
surveillance of diseases
Biologic actions of CKs
• Anti-bacteria: IL-1 , TNF, IL-6, and IL-12,
• Anti-virus:type I IFN
Biologic actions of CKs
• Mediate and regulate adaptive immunity :
Stimulating the proliferation of
lymphocytes：IFN-,IL-2 ,IL-4 ,IL-5)
Stimulating the development of
lymphocytes: IL-12, IFN- ,IL-4.
Increasing the activity of effective cells：
IFN-  , IL-2 .
Inhibiting immune response: TGF-,IL-10
Comparative Features of the Cytokines
of Innate and Adaptive Immunity
Features
Innate immunity
Adaptive immunity
Examples
TNF-α, IL-1, IL-12, IFN-γ *
IL-2, IL-4, IL-5, IFN-γ *
Major cell source
Macrophages, NK cells
T lymphocytes
Principal physiologic
functions
Mediators of innate
immunity and inflammation
(local and systemic)
Adaptive immunity:
regulation of lymphocyte
growth and differentiation;
activation of effector cells
(macrophages, eosinophils,
mast cells)
Stimuli
LPS (endotoxin), bacterial
peptidoglycans, viral RNA,
T cell-derived cytokines
(IFN-γ)
Protein antigens
Cyclosporine
Amounts produced Local or May be high; detectable in
systemic effects
serum Both
Generally low; usually
undetectable in serum
Usually local only
Roles in disease
Systemic diseases (e.g.,
septic shock)
Local tissue injury (e.g.,
granulomatous
inflammation)
Inhibitors of synthesis
Corticosteroids
, FK-506
*IFN-γplays important roles in innate and adaptive immunity.
Biologic actions of CKs
• Stimulate hematopoiesis
SCF → stem cells
CSF → granulocyte and monocyte
IL-4 and GM-CSF →dendritic cells
EPO → erythrocyte
IL-11 and TPO →platelet
IL-7 → formation of pro-T
• Angiogenesis
Biological product of cytokines or
cytokines receptor analogs
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rIFN-α:Intron-A, Referon-A
rIFN-β:Prokine
rEPO:Epogen
rGM-CSF:Acimmune
Human TNF McAb:HumiraTM