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.

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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