医学免疫学课件：Lu 细胞因子 EN

1、Cytokines,Cytokines are low-molecular weight regulatory proteins （glycoproteins) secreted by white blood cells and various other cells in the body in response to a number of stimuli. These proteins mediate and regulate immune and inflammatory reactions.,Definition,1. General Properties of Cytokines

2、2. Functional Categories of cytokines 3. Cytokine receptors and signal transduction 4. Cytokines that mediate and regulate innate immunity 5. Cytokines that regulate Adaptive Immunity 6. Cytokines that stimulate Hematopoiesis 7. Cytokine related diseases 8. Therapeutic Use of cytokines,Cytokines,1.1

3、 Cytokine secretion is a brief, self-limited event; 1.2 The actions of cytokines are often pleiotropic and redundant; 1.3 Cytokines often influence the synthesis and actions of other cytokines ;,1. General Properties,1.4. Cytokine actions may be local and systemic ; 1.5. Cytokines initiate their act

4、ions by binding to specific membrane receptors on target cells; 1.6. The cellular responses to most cytokines consist of changes in gene expression in target cells, resulting in the expression of new functions in the target cells,1. General Properties,IL2 secretion by CD4 T cells upon TCR engagement

5、,Cytokine secretion upon CpG treatment,1.1 Cytokine secretion is a brief, self-limited event;,1. Absent from unstimulated cells. 2. Rapid transcriptional activation with stimulation. 3. Can have post-translational control; 4. Rapid secretion. 5. Short-lived transcripts and proteins. 6. Transcription

6、 ceases when stimulus abates.,One cytokine can target different target cells,1.2 The actions of cytokines are often pleiotropic and redundant,Different cytokines can exert similar effect,1.2 The actions of cytokines are often pleiotropic and redundant,Cytokines can work together or against each othe

7、r,1.3 Cytokines often influence the synthesis and actions of other cytokines ;,One cytokine can induce another cytokine and so on.,1.3 Cytokines often influence the synthesis and actions of other cytokines (Cascade effect),Cytokine Network,1.4 Cytokine actions may be local and/or systemic,1.5 Cytoki

8、nes initiate their actions by binding to specific membrane receptors on target cells. 1.6 The cellular responses to most cytokines consist of changes in gene expression in target cells, resulting in the expression of new functions in the target cells,Cytokine families based on their biological funct

9、ion similarity： 2.1 Interleukines 2.2 Interferons 2.3 Colony Stimulating Factors 2.4 TNF family 2.5 Chemokines 2.6 Transforming Growth Factors 2.7 Other cytokines (MIF, c-kit ligand, LIF , OsM CNTF etc.,2. Functional Categories of cytokines,1. First seen to be expressed by white blood cells (leukocy

10、tes), The term interleukine, (inter-) as a means of communication, (-leukin) deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes. 2. It has since been found that interleukins are produced by a wide variety of body cells. The function of the immune syst

11、em depends in a large part on interleukins, And rare deficiencies of a number of them have been described, all featuring autoimmune diseases or immune deficiency. The majority of interleukins are synthesized by helper CD4+ T lymphocytes, as well as through monocytes, macrophages, and endothelial cel

12、ls. They promote the development and differentiation of T, B, and hematopoietic cells.,2.1 Interleukins (IL),Interferons (IFNs) are natural cell-signaling proteins produced by the cells of the immune system in response to challenges such as viruses, parasites and tumor cells. Interferons assist the

13、immune response by inhibiting viral replication within host cells, activating immune cells (natural killer cell and macrophages), increasing antigen presentation to T Lymphocytes, and increasing the resistance of host cells to viral infection. There are 3 known classes of interferons; type I, type I

14、I and type III. All classes are very important in fighting viral infections. Their presence also accounts for some of the host symptoms to infections, such as sore muscles and fever.,2.2 Interferons (IFNs),2.3 Colony-stimulating factor Colony-stimulating factors (CSFs) are secreted glycoproteins whi

15、ch bind to receptor proteins on the surfaces of hemopoietic stem cells and thereby activate intracellular signaling pathways which can cause the cells to Proliferate and differentiate into a specific kind of blood cell (usually white blood cells）。,The name “colony-stimulating factors” comes from the

16、 method by which they were discovered. Hemopoietic stem cells were cultured in semi solid matrix which prevents cells from moving around, so that if a single cell starts proliferating, all of the cells derived from it will remain clustered around the spot in the matrix where the first cell was origi

17、nally located, and these are referred to as colonies. It was therefore possible to add various substances to cultures of hemopoietic stem cells and then examine which kinds of colonies (if any) were stimulated by them. The substance which was found to stimulate formation of colonies of macrophages,

18、for instance, was called macrophage colony-stimulating factor, for granulocytes, granulocyte colony-stimulating factor, and so on.,2.3 Colony-stimulating factor,Tumor necrosis factors (or the TNF-family) refers to a group of cytokines family that can cause cell death. TNF acts via the TNF Receptor (

19、TNF-R) and is part of the extrinsic pathway for triggering apoptosis. Tumor necrosis factor-alpha (TNF-) is the most well-known member of this class, and sometimes referred to when the term tumor necrosis factor is used. Tumor necrosis factor-beta (TNF-), also known as lymphotoxin is a cytokine that

20、 is induced by interleukin 10 3,2.4 Tumor necrosis factors,Chemokines (Greek -kinos, movement) are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines. Proteins a

21、re classified as chemokines according to shared structural characteristics such as small size (they are all approximately 8-10 kilodaltons in size), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape.,2.5 Chemokines,28,17,2,1,Receptors

22、:,2.5 Chemokines,Transforming growth factor (sometimes referred to as Tumor growth factor, or TGF) is used to describe two classes of polypeptide growth factors, TGF and TGF. TGF is upregulated in some human cancers. It is produced in macrophages, brain cells, and keratinocytes, and induces epitheli

23、al development. TGF exists in three known subtypes in humans, TGF1, TGF2, and TGF3. These are upregulated in Marfans syndrome and some human cancers, and play crucial roles in tissue regeneration, cell differentiation, embryonic development, and regulation of the immune system.,2.6 Transforming grow

24、th factor (TGF),Pleiotropic effects of TGF- on leukocytes. All leukocytes produce and respond to TGF-. The yin-yang symbol illustrates the fact that TGF- exerts both stimulatory and inhibitory effects on immune cells. Selected immunological processes regulated by TGF- are depicted (MC, mast cell; EO

25、, eosinophil; MO/M, monocyte/macrophage).,TGF- blocks T cell proliferation by inhibiting IL-2 production via Smad3 and by downregulating the expression of cyclinD2 and E, CDK4, and c-myc. TGF- inhibits differentiation of Th1 and Th2 cells through suppressing the expression or function of T-bet/Stat4

26、 and GATA-3/NFAT. Mechanisms involved in TGF- inhibition of CTL differentiation are not well understood, although inhibition of c-myc and T-bet expression is suggested. TGF- induces FoxP3 expression and the generation of Tregs. TGF- also prevents T cell activation-induced cell death (AICD) through i

27、nhibiting c-myc-mediated FasL expression and other unknown mechanisms,TGF- regulation of T cell responses,Ming Lis work,Ming Li, Richard Flavell ， Sloan Kettering Yale,To study the precise function and mechanism of TGF-beta control of immune responses, we used a tissue-specific gene-targeting techni

28、que to inactivate TGF-beta and TGF-beta receptor in various cell types in mice. These studies revealed TGF-beta as a critical regulator of T lymphocyte development, homeostasis, tolerance to self-antigens, and differentiation during the immune responses.,3. Cytokine Receptors,Immunoglobin domain Rec

29、eptors in this family has the immunoglobin domain named after the immunoglobulin molecules,This receptor family have conserved amino acid sequence motifs in the extracellular domain consisting of four positionally conserved cysteine residues (CCCC) and a conserved sequence of tryptophanserine-( any

30、amino acid)- tryptophan-serine (WSXWS,where X is the nonconserved amino acid). The receptors for all the cytokines classified as hematopoietins belong to the class I cytokine receptor family, which also is called the hematopoietin receptor family.,The class II cytokine receptors possess the conserve

31、d CCCC motifs, but lack the WSXWS motif present in class I cytokine receptors. Initially only the three interferons, , , and , were thought to be ligands for these receptors. However, recent work has shown that the IL-10 receptor is also a member of this group.,Tumor necrosis factor receptors (TNFRs

32、) are cytokine receptors that binds TNFs (TNF). They were also called death receptors since they can transduce signals lead to cell death,Chemokine receptors are receptors of chemokines. There have been 19 distinct chemokine receptors described in mammals. They each have a 7 transmembrane (7TM) stru

33、cture and couple to G-Protein for signal transduction within a cell, making them members of a large protein family of G protein-coupled receptors. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium (Ca2+) ions (calcium signaling).

34、 This causes cell responses, including the onset of a process known as chemotaxis that traffics the cell to a desired location within the organism.,Another feature common to most of the hematopoietin (class I cytokine) and the class II cytokine receptor families is multiple subunits, often including

35、 one subunit that binds specific cytokine molecules and another that mediates signal transduction.,Cytokines have numerous functions. Mediators and regulators of Innate Immunity Mediators and regulators of adaptive immunity Stimulators of hematopoiesis,The innate immunity comprises the cells and mec

36、hanisms that defend the host from infection, in a non-specific manner. Innate immune systems provide immediate defense against infection, but does not confer long-lasting or protective immunity to the host. The adaptive immune system is composed of highly specialized, systemic cells and processes th

37、at eliminate or prevent pathogenic challenges. It can recognize and remember specific pathogens (to generate immunity), and to mount stronger attacks each time the pathogen is encountered. It is adaptive immunity because the bodys immune system prepares itself for future challenges.,Main Cytokines i

38、n innate immunity,TNF Interleukin-1 Interleukin-12 Type I interferons Interleukin-10 Interferon- (IFN-):,TNF Mediator of acute inflammatory response to gram-negative bacteria and other infectious microbes. Major cellular source is activated mononuclear phagocytes (Macrophage stimulated with LPS); Ca

39、n be membrane protein or released (trimer),Signaling by TNF receptors:,Recruitment of neutrophils and monocytes to sites of infection and activate these cells to eradicate microbes; Large amount of TNF can cause systemic clinical and pathological abonomalities Septic shock (endotoxin shock): vascula

40、r collapse.,Biological Actions of TNF,Interleukin-1 (IL-1): Mediator of inflammatory response to infectious microbes. Major cellular source is activated mononuclear phagocytes; Two forms IL-1 and IL-1 (30% homologous), IL-1 need to be cleaved to be active (ICE：IL-1- convertingenzyme) Similar effect

41、as TNF,Produced by activated mononuclear phagocytes and dedritic cells Stimulate IFN production by NK and T lymphoctyes. Enhance cytolytic functions of activated NK and CTL cells. Is a link between innate and adaptive immunity.,Interleukin-12,Type I interferons: IFN- (20) and IFN- Stimulated by vira

42、l infection, mediate early innate immune response to viral infections- establishment of “antiviral state” Biological Actions: Inhibits viral replication Increase expression of MHC I Stimulate the development of Th1 cells Inhibits the proliferation of many cell time.,Interleukin-10: IL10 is an inhibi

43、tor of activated macrophages and dedritic cells and is thus involved in the control of innate immune reactions and cell-mediated immunity. Produced by activated macrophages. Inhibits the production of IL12; Inhibits the expression of costimulators and MHC II. IL10-/- develop inflammatory bowel disea

44、se.,Interferon- (IFN-): IFN- is the principal macrophage-activating cytokine that provide the means by which T lymphocytes and NK cells activated macrophages to kill phagocytosed microbes. IFN- stimlates expression of MHC I and MHC II molecules and costimulators on APCs.,Cytokines mediate and regula

45、te adaptive immunity Interleukin-2 Interleukin-4 Interferon- Transforming Growth Factor-,Interleukin-2: IL2 is a growth factor for antigen-stimulated T-lymphocytes and is responsible for T cell clonal expansion after antigen recognition. Promote proliferation of antigen-specific T cells; Promote the

46、 proliferation and differentiation of other immune cells; Essential for the development and proliferation of CD4+FoxP3+ Tregs (a subfamily of T helper cells exert regulatory function).,Interleukin-4 (IL4): IL4 is the major stimulus for the production of IgE antibodies and for the development of Th2

47、cells from nave CD4+ helper T cells. Biological Actions: Stimulate B cell Ig heavy chain class switching to IgE isotype Stimulate Th2 cells Inhibit Th1 differentiation and cell-mediate immune response,Interferon- (IFN-): The role of IFN- in adaptive immunity is to promote the differentiation of Th1

48、helper cell and cell-mediated immune reaction. IFN- can also inhibite the development of Th2 helper cells,Transforming Growth Factor- (TGF-): Inhibit the proliferation and action of lymphocytes and other leukocytes Stimulate the differentiation of Tregs and Th17 cells (with IL6).,Th differentiation governed by signal III (cytokines),Signal I,Signal II,Signal III,Revised Th Differentiation,Th17 and Treg Cells,Th17 (CD4+, FoxP3-) IL-17 is a pro-inflammatory cytokine Promotes secretion of pro-inflammatory cytokines (I