Medical ImmunologyMedical Immunology
Cytokines,CKs
陈建忠 浙江大学免疫学研究所
CytokinesCytokines
• Concept
• Characteristics
• Classification
• Cytokine receptor
• Biologic activity
Introduction to cytokinesIntroduction 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 cytokineIntroduction to cytokine
Nomenclature Nomenclature OldOld :: monokine,monokine,lymphokine,lymphokine, NewNew :: colony stimulating factor, colony stimulating factor,
interleukininterleukin, interferon, tumor , interferon, tumor necrosis factor,growth factor, necrosis factor,growth factor, chemokinechemokine
Introduction to CKsIntroduction 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 CKsIntroduction 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 CKsIntroduction 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 cytokineIntroduction 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.
Cyto
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netw
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Categories of CKsCategories of CKs• Interleukin (IL)• Interferon (IFN)• Tumor necrosis factor (TNF)• Colony stimulating factor (CSF)• Chemokine• Growth factor(GF)
interleukin, ILinterleukin, 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-2IL-2
interferon, IFNinterferon, 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- 的 抗 病 毒 作 用
病毒
病毒复制 抑制病 毒复制
信号转导
IFN-
IFN-诱导蛋白诱导刺激
胞核 胞核
Tumor necrosis factor, TNFTumor 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, CSFColony-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 .
ChemokineChemokine
• 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).
ChemokineChemokine
• IL-8 CXC neutrophils
• MCP-1 CC monocyte
• Lymphotactin C lymphocyte
• Fractalkine CX3C lymphocyte
Growth factor(GF)Growth factor(GF)
• Promoting the proliferation and
differentiation of cells;
• Including TGF-
、 EGF 、 VEGF 、 FGF 、 NGF 、 PD
GF , etc.
cytokine receptorcytokine 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
CCK receptorK receptor
• Multi-subunit receptor one for cytokine binding another for cytokine signaling
CCK ReceptorK Receptor
• Common receptor subunit There is same receptor
subunit for cytokine signaling among the different cytokine receptors. e.g. IL-2Rγ
CK ReceptorCK Receptor
CK ReceptorsCK Receptors
• Soluble cytokine receptors Functions :
①antagonist of CKs ; ②delivery tools of CKs ; ③as a index of diagnosis and surveillance of diseases
Biologic actions of CKsBiologic actions of CKs
• Anti-bacteria: IL-1 , TNF, IL-6, and IL-12,
• Anti-virus:type I IFN
Biologic actions of CKsBiologic 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
Cyclosporine
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
Amounts produced Local or systemic effects
May be high; detectable in 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 CKsBiologic 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 Biological product of cytokines or cytokines receptor analogscytokines receptor analogs
• rIFN-α:Intron-A, Referon-A• rIFN-β:Prokine• rEPO:Epogen• rGM-CSF:Acimmune• Human TNF McAb:HumiraTM