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Cytokines Xiaojian Wang Institute of Immunology Zhejiang University [email protected] Introduction to cytokines Cytokines are small soluble proteins that mediate immune and inflammatory reactions and are responsible for communications between leukocytes or between leukocytes and other cells via binding the receptor. 是除免疫球蛋白和补体的另一类特 异性免疫效应物质 • Cytokines work by binding to a target cell. Therefore, for a cytokine to have an effect, two things have to occur: – The cytokine needs to be present there – The target cell needs to have a receptor on its surface • Therefore, regulation can occur at either step. Nomenclature According to their source 1) Lymphokine 2) Monokine According to their function 1) Colony stimulating factor 2) Interleukin 3) Interferon 4) Tumor necrosis factor 5) Growth factor 6) Chemokine Manner of action 1) Autocrine: IL-2 Th 2) Paracrine : IL-12 DC 3) Endocrine: IL-1, TNF- Th Th Under certain circumstances (e.g. septic shock), large amounts of CKs (such as TNF-) are produced, they may be active distant from their site of secretion. Manner of action Cytokines 1. General Properties of Cytokines 2. Functional Categories of cytokines 3. 4. 5. 6. Cytokine receptors Biologic function of Cytokines Cytokine related diseases Therapeutic Use of cytokines 1. General Properties 1.1. The actions of cytokines are often pleiotropic and redundant; 1.2. Cytokines often influence the synthesis and actions of other cytokines ; 1.3. Cytokine actions may be local and systemic ; 1.4. Cytokines initiate their actions by binding to specific membrane receptors on target cells; 1.5. The cellular responses to most cytokines consist of changes in gene expression in target cells, resulting in the expression of new functional protein in the target cells. 1.1 The actions of cytokines are often pleiotropic and redundant One cytokine can target different target cells 1.1 The actions of cytokines are often pleiotropic and redundant Different cytokines can exert similar effect Cytokine Network 1.2 Cytokines often influence the actions of and synthesis of other cytokines; Cytokines can work together or against each other 1.2 Cytokines often influence the actions and the synthesis of other cytokines (Cascade effect) One cytokine can induce another cytokine and so on……. 1.3 Cytokine actions may be local and/or systemic 1.4 Cytokines initiate their actions by binding to specific membrane receptors on target cells. 1.5 The cellular responses to most cytokines consist of changes in gene expression in target cells, resulting in the expression of new functional protein in the target cells General Properties 1.Pleiotropism 2.Redundancy 3.Synergy 4.Antagonism 5.Network 2. Functional Categories of cytokines CKs are classified into 6 functional categories 2.1 2.2 2.3 2.4 2.5 2.6 Interleukines Interferons Colony Stimulating Factors TNF family Chemokines Transforming Growth Factors 2.1 Interleukins (IL) 1.Cytokines produced by leukocytes and act on leukocytes 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. The interleukins are produced by a wide variety of body cells. The function of the immune system depends in a large part on interleukins, The majority of interleukins are synthesized by helper CD4+ T lymphocytes, as well as through monocytes, macrophages, and endothelial cells. They promote the development and differentiation of T, B, and hematopoietic cells. And rare deficiencies of a number of them have been described, all featuring autoimmune diseases or immune deficiency. Interleukin, IL IL 1~38 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 IL-4 2.2 Interferons (IFNs) Interferons (IFNs) are natural cell-signaling proteins produced by the cells of the immune system to challenges such as viruses, parasites and tumor cells. Groups Type I IFN: IFN- and IFN- The major source is leukocytes (PDC), fibroblasts and virus infected cells. Help prevent the spread of virus to uninfected cells. Type II IFN: IFN- IFN- is produced by activated T cells and NK cells. Its main function is immune regulation. IFN- 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- 2.3 Colony-stimulating factor Colony-stimulating factors (CSFs) are secreted glycoproteins which 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)。 2.3 Colony-stimulating factor The name “colony-stimulating factors” comes from the 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 originally 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, for instance, was called macrophage colony-stimulating factor, for granulocytes, granulocyte colony-stimulating factor, and so on. 2.4 Tumor necrosis factors • TNF was originally identified (and was so named) as a substance that can cause the necrosis of tumors in vivo. • TNF- and TNF- TNF- is produced by LPS-stimulated mononuclear phagocytes and activated T cells. Involved in inflammation. TNF- is also termed lymphotoxin (LT), and is produced mainly by activated T cells. 2.5 Chemokines Chemokines 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. Chemokines share structural characteristics such as small size (all of them are all about 8-10 kilodaltons in size), and all of them have four cysteine residues in conserved locations that are key to forming their 3-dimensional shape. 2.5 Chemokines About 50 different members. 2 lymphotactin 28 1 17 2.6 Transforming growth factor (TGF) Transforming growth factor (sometimes referred to as Tumor growth factor, or TGF) is used to describe two classes of polypeptide growth factors, TGFα and TGFβ. TGFα is upregulated in some human cancers. It is produced in macrophages, brain cells, and induces epithelial development. TGFβ exists in three known subtypes in humans, TGFβ1, TGFβ2, and TGFβ3. These are upregulated in Marfan's syndrome and some human cancers, and play crucial roles in tissue regeneration, cell differentiation, embryonic development, and regulation of the immune system. Pleiotropic effects of TGF-β on leukocytes. All leukocytes produce and respond to TGF-β. The yin-yang symbol illustrates the fact that TGF-β exerts both stimulatory and inhibitory effects on immune cells 3. Cytokine Receptors 3.1 Five families Immunoglobin domain Receptors 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 tryptophan-serine-( any 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 conserved CCCC motifs, but lack the WSXWS motif which is present in class I cytokine receptors. Initially only the three interferons, were thought to be ligands for these receptors. However, recent work has shown that receptors for the IL-10 ,IL19 are also members of this group. Tumor necrosis factor receptors (TNFRs) 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) structure and couple to G-Protein for signal transduction within a cell, making this kind of receptor belong to 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). This causes cell responses, including the onset of a process known as chemotaxis that traffic the cell to a desired location within the organism. 3.2 Multi-subunit receptor and common receptor subunit • Multi-subunit receptor one for cytokine binding another for cytokine signaling • Common receptor subunit There is same receptor subunit for cytokine signaling among the different cytokine receptors. e.g. IL-2R The same receptor subunit for cytokine signaling among the different cytokine receptors. e.g. IL-2R Another feature common to most of the hematopoietin (class I cytokine) is multiple subunits, often including one subunit that binds specific cytokine molecules and another that mediates signal transduction. 3.3 Soluble cytokine receptors • Is the extracellular part of the receptor • Functions 1) antagonist of CKs: competitively bind to CK 2) delivery tools of CKs 3) index of diagnosis and prognosis of diseases: sIL2R 4. 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 mechanisms that defend the host from infection, in a non-specific manner. Innate immune systems provide immediate defense against infection, but does not confer longlasting or protective immunity to the host. The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic challenges. It can recognize and remember specific pathogens and confer long-lasting or protective immunity to the host. It is adaptive immunity because the body's immune system prepares itself for future challenges. 4.1 Main Cytokines in innate immunity 抗细菌作用: TNF, IL-1,IL-6, IL-8 抗病毒作用: IFNa/b IFN-Y, IL-12, MCP TNF Interleukin-1 Interleukin-12 Type I interferons Interleukin-10 Interferon-γ (IFN-γ): TNF Mediator of acute inflammatory response to gramnegative bacteria and other infectious microbes. Mainly produced by mononuclear phagocytes (Macrophage stimulated with LPS); Can be membrane protein or released (trimer) Biological Actions of TNF In the low quantities, TNF recruit neutrophils and monocytes to sites of infection and activate these cells to eradicate microbes; Large amount of TNF can cause systemic clinical and pathological abnormalities such as Septic shock (endotoxin shock): vascular collapse. Interleukin-1 (IL-1): Mediator of inflammatory response to infectious microbes. Mainly produced by activated mononuclear phagocytes; Two forms IL-1α and IL-1β (30% homologous), IL-1 β need to be cleaved to be active Similar effect as TNF Interleukin-12 Produced by activated mononuclear phagocytes and dendritic 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. Type I interferons: IFN-α (20) and IFN-β Stimulated by viral infection, mediate early innate immune response to viral infectionsestablishment of “antiviral state” Biological Actions: Inhibits viral replication Stimulate the development of Th1 cells Interleukin-10: IL10: produced by activated macrophages, is an inhibitor of activated macrophages and dendritic cells and inhibits the production of IL12; IL10 is thus involved in the control of innate immune reactions and cellmediated immunity. IL-10 inhibitroy factor . Interferon-γ (IFN-γ): IFN-γ is the principal macrophage-activating cytokine, T lymphocytes and NK cells produced the IFN-γ and activated macrophages to kill phagocytosed microbes. 4.2 Cytokines mediate and regulate adaptive immunity Interleukin-2 Interleukin-4 Interferon-γ Transforming Growth Factor-β Interleukin-2: IL-2 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 proliferation and differentiation of other immune cells; Interleukin-4 (IL4): IL4 is the major stimulus for the production of IgE antibodies and for the development of Th2 cells from naïve 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-γ (IFN-γ): The role of IFN-γ in adaptive immunity is to promote the differentiation of Th1 helper cell and cell-mediated immune reaction. IFN- γ can also inhibit the development of Th2 helper cells IFN-γ stimulates the expression of MHC I and MHC II molecules and costimulators on APCs. Transforming Growth Factor-β (TGF-β): Produced by Ts, macrophages, and other cell types It inhibits the proliferation of T cells and the activation of macrophages. Acts on PMNs and endothelial cells to block pro-inflammatory cytokine effects Inhibitory factor: IL-10 ,TGF-β 4.3 Cytokines in hematopoiesis 5.Cytokine and disease Cytokine-related diseases 1. 细胞因子风暴: Bacterial septic shock endotoxins (cell walls) stimulate production of IL-1 and TNF- 2. 致热与炎症病理损害: IL-1, IL-6 3. 肿瘤的发生与逃逸 Cancers of lymphoid system- overproduction of cytokines such as IL-6 (B-cell) or IL-5 (Hodgkin’s disease) or IL-2 (adult T-cell leukemia). IL-10, TGF-B 抑制机体的免疫功能。 4. 免疫系统相关疾病 1.)超敏反应 IL-4。 2.)自身免疫病:类风湿关节炎,TNF-a 3.) 免疫缺陷病 Chagas ’ disease (parasitic)- suppression of -subunit of IL-2 receptor 4.)器官移植排斥反应: IL-1, IL-2,TNF-a 6. Cytokine therapies Interferons IFN-- certain types of tumors IFN-- multiple sclerosis these are antiviral IFN-- chronic granulomatous disease IL-2- certain types of cancer infusion LAK (lymphokine-activated killer) cells TILs (tumor-infiltrating lymphocytes) GM-CSF- immune deficiencies TNF (tumor necrosis factors) TNF- and In some cases inhibit proliferation of tumor cells but not normal cells May damage vascular endothelial cells in tumors, thus inhibiting blood supply to the tumor Anti-TNF-a antibody Considerations when Considering Therapeutic Applications • Normally, cytokines are transferred from one cell to another over a very short distance. – Probably yields very high doses in that local environment that are difficult to mimic clinically • Interactions with other cytokines are undoubtedly important. • Cytokines have a short half-life and are degraded quickly. Requires continual administration. • Cytokines have many different effects (pleiotropy); therefore, often see unexpected and undesirable sideeffects. Sample question • A. B. C. D. Which of the following cytokines plays an inhibitory effect on macrophages and dendritic cells terminating inflammatory response? IL-2 IL-4 IFN- IL-10 Answer=D Sample question • Which of the following cytokines promote the differentiation of Th1 helper and inhibit the development of Th2 helper cells ? A. IFN-γ B. IL-4 C. IFN- D. IL-2 Answer=A Characteristic of cytokine to perform their biological functions? Thanks for your attention!