医学免疫学英文版课件：Chapter 7 cytokine

1、MEDICAL IMMUNOLOGYChapter 7 CytokinesCytokinesGeneral properties Functional Categories Biological functionsCytokine receptorsCytokine and clinical applicationCytokines are small polypeptides produced in response to microbes and other antigens that mediate and regulate immune and inflammatory reactio

2、ns.Lymphokine (淋巴因子): IL-2、3、4、5、6、9、10、11、12、13、 TNF-、IFNMonokine (单核因子): IL-1、8、TNF-、 IFN-Cytokine (细胞因子)1、StructureLow molecular weight（15-30kD）GlycoproteinMonomer, dimer (IL-12, IFN-), trimer (TNF-)Soluble, membrane-bounded (TNF-)Mature, precursor (IL-1, IL-18)General Properties of CytokinesProp

3、erties of Cytokines2、Production multiple sources: cytokines come from many kinds of cells-activated immune cells, matrix cells and some tumor cells.Cytokine production is a brief and self-limited event.Cytokines often influence the synthesis and actions of other cytokines3、ActionBinding to specific

4、membrane receptors High efficiency：Kd 10-10-10-12 Antibody and antigen: Kd 10-7-10-11 MHC-peptide and TCR: Kd 10-5-10-7(Kd 10-10 to 10-12)Properties of CytokinesPleiotropism（多效性): one cytokine having multiple effects on diverse cell typesRedundancy (重叠性): multiple cytokines having the same or overla

5、pping actionsSynergy (协同效应): two or more cytokines having greater than additive effects Antagonism (拮抗效应): one cytokine inhibiting the action of anotherTH1MjIL- 4 骨髓基质细胞IL-1 IL-6 IL-7 SCF 造血干细胞IL-1 IL-6 IL-11 TNF-a GM-CSF G-CMF M-CSF单核细胞TH2B中性粒细胞嗜酸性粒细胞IL-1 IL-8 TNF-aIL-1 TNF-aIL-10 IL- 4IL- 4 IL-6 I

6、L-10 IL-13 IL-4 TGF-bIL-4 IL-5 IL-6 IL-13 IL-10 TGF-bIL-4IL-4内皮细胞IL-4TcIL-4IL-2 IFN-gIL-10 IL-13 IL-4 NK1+T NK 细胞IFN-gIL-2IL-2 IFN-gIL-2IL-2 IL-12G-CMF IFN-g GM-CSF IL-12IL-1 TNF-a TGF-b PDGF FGF M-CSF GM-CSF 内皮细胞纤维母细胞下 丘 脑IL-1 TNF-aM-CSF GM-CSF IL-1 IL-6 TNF-aIL- 4IL- 6IL- 4 autocrineendocrine血液循环远

7、距离作用 paracrine作用于邻近细胞作用于分泌细胞自身4、Mode of actionAutocrine: Acting on the same cells that produced themParacrine:Acting on a nearby cellsEndocrine: Acting on cells at a distanceProperties of Cytokines Functional Categories of CytokinesThere are perhaps as many as 200 cytokines that act in the immune sy

8、stem. Be grouped by their functions and structures.Interleukin （白细胞介素, ILs）Interferon （干扰素, IFNs）Tumor necrosis factor （肿瘤坏死因子, TNFs）Colony stimulating factor （集落刺激因子, CSFs）Chemokine（趋化性细胞因子）Transforming growth factor（转化生长因子, TGF )1. InterleukinThe term was used to describe cytokines produced by leu

9、kocytes (e.g., macrophage or T cells) and act on other leukocytes. Many cytokines that are synthesized only by leukocytes and act only on leukocytes are not called interleukins.Many cytokines can be produced by other cell populations.IL-135Categories of Cytokines2. InterferonDivided into type interf

10、eron (IFN- and IFN-) and type interferon (IFN-).Type interferons mediate the early innate immune response to viral infections. Type interferons mainly produced by plasmacytoid dendritic cells (pDC) and mononuclear phagocytes.Categories of CytokinesIFN- is the principal macrophage-activating cytokine

11、 and serves critical functions in innate immunity and in adaptive cell-mediated immunity against intracellular microbes.IFN- is produced by NK cells and T cells.3. Tumor necrosis factorTumor necrosis factor (TNF) can induce tumor necrosis.Divided into TNF- and TNF-(lymphotoxin).The major source of T

12、NF are from activated mononuclear phagocytes. Other cells including T cell and NK cell can also secret TNF.Categories of CytokinesTNF is a trimer.Mediate inflammation and regulate immune responses.4. Colony stimulating factor Colony stimulating factors (CSFs) drive the differentiation and expansion

13、of bone marrow stem and progenitor cells.Categories of Cytokines5. ChemokineAll chemokines are 8 to 12-kD polypeptides that contain internal disulfide loops.Chemokines can stimulate leukocyte movement and regulate the migration of leukocyte.T cells, macrophage, fibroblast, endothelial cells, epithel

14、ial cell et al.Categories of CytokinesMacrophage, lymphocyte et al.Neutrophil6. Transforming growth factorsTransforming growth factors are cytokines which can regulate the growth and differentiation of their target cells.Including TGF-and TGF-TGF-can bind to EGFR for signaling.TGF-can bind to specia

15、l TGF-receptor for signaling.TGF-inhibits the proliferation and effector functions of T cells and the activation of macrophages.Categories of Cytokines Biological functions of cytokines1. Take part in innate immunity2. Take part in adaptive immunity3. Mediate inflammation4. Stimulate hematopoiesisBi

16、ological function1. Take part in innate immunityProduced mainly by mononuclear phagocytes including IFN, TNF, IL-1, IL-12, and so on.IFN- and IFN- are produced in response to viral infection by the infected cells and act on their target cells to inhibit viral replication.IFN-activates macrophages to

17、 kill phagocytosed microbes.IL-2 promotes the proliferation and differentiation of T cells and NK cells.IL-12 enhances the cytotoxic function of activated NK cells. Functions of type IFN in viral infection2. Take part in adaptive immunityProduced mainly by activated T cells including IL-2, IL-4, IL-

18、5, IL-6, IL-10, TGF-, IFN-, and so on.IL-2: T cell proliferation and activationIL-4, 5, 6: B cell proliferation and differentiationIFN-: CD4+ T cell activationIL-10, TGF-: negative regulator of immune activationBiological functionFunctions of IFN-Functions of IL-12Functions of IL-2 Functions of IL-4

19、 Cytokines have an important role to mediate Th subset differentiation.Cytokines have an important role in generation of antibody class diversity.3.Mediate inflammationIL-1, TNF-: induce adhension molecule expressionChemokine: migration of inflammatory cell to infection siteActivate phagocytosisBiol

20、ogical function4. Stimulate hematopoiesisIL-3, SCF, G-SCF, GM-SCFThese cytokines act on hematopoietic stem cells resulting to generation of blood cells.Biological function Cytokine ReceptorsCommon properties of cytokine receptorsThe receptor consists of extracellular domain, transmembrane domain and

21、 cytoplasmic domain.All cytokine receptors consist one or more transmembrane proteins.Cytokine ReceptorsCytokine ReceptorsMany different cytokine may use the same intracellular signaling peptide.These receptors contain only extracellular domain.Can compete with memebrane-binding receptors for bindin

22、g to the cytokines, resulting to inhibition of the effects of the cytokines. Alternative splicing of mRNASoluble cytokine receptorsCytokine Receptors1. Type I cytokine receptors (called hemopoietin receptors)contains one or more copies of a domain with two conserved pairs of cysteine residues and a

23、membrane proximal sequence of tryptophan-serine-X-tryptophan-serine(WSXWS)Cytokine Receptors2. Type cytokine receptors (Interferon receptors)Similar to Type I cytokine receptors with conserved cysteine, but no WSXWS motif.Cytokine Receptors3. Type cytokine receptors(TNF receptors)Contain conserved t

24、rimeric, cysteine-rich extracellular domainsCytokine Receptors4. Immunoglobulin receptor superfamilyContain one or more immunoglobulin motifCytokine Receptors5.G protein-coupled receptors (chemokine receptors)Contain seven-transmembrane -helical motif and need G protein for activationCytokine ReceptorsCytokine and clinical application Cytokine and diseaseSeptic Shock: TNF-, IL-1类风湿关节炎 强直性脊柱炎 TNF-银屑病关节炎H5N1: cytokine storm- TNF-, IL-1, IL-6, IL-12, IFN et al.Tumor: TGF- Prevention and treatmen