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Cytokines Linrong Lu ZJU Instiitute of Immunology [email protected] l http://mypage.zju.edu.cn/personnelCard/llr Definition Cytokines C t ki are low-molecular l l l weight i ht regulatory proteins ( glycoproteins) secreted by white blood cells and various other cells in the body in response p to a number of stimuli. These proteins mediate and regulate immune and inflammatory reactions. Cytokines 1. General Properties of Cytokines 2. Functional Categories of cytokines 3. Cytokine receptors and signal transduction 4. Cytokines y that mediate and regulate g innate immunity 5. Cytokines that regulate Adaptive Immunity 6. Cytokines y that stimulate Hematopoiesis p 7. Cytokine related diseases 8. Therapeutic Use of cytokines 1 General Properties 1. 1.1 Cytokine secretion is a brief, self-limited event; 1.2 The actions of cytokines are often pleiotropic and r un ant; redundant; 1.3 Cytokines often influence the synthesis and actions of f other h cytokines k ; 1 General Properties 1. 1.4. Cytokine actions may be local and systemic ; 1.5. Cytokines initiate their actions by binding to specific membrane receptors on target cells; 1.6. The cellular responses p to most cytokines y consist of changes in gene expression in target cells, resulting in the expression of new functions in the target cells ll 1.1 Cytokine secretion is a brief, self-limited event; Cytokine secretion upon CpG treatment IL2 secretion by CD4 T cells upon TCR engagement 1. 1 2. 3. 4. 5. 6. Ab Absent nt from f m unstimulated n tim l t d cells. ll Rapid transcriptional activation with stimulation. Can have post-translational control; Rapid p secretion. Short-lived transcripts and proteins. Transcription ceases when stimulus abates. 1.2 The actions of cytokines are often pleiotropic and redundant One cytokine can target different target cells 1.2 The actions of cytokines are often pleiotropic and redundant Different cytokines can exert similar effect 1.3 Cytokines often influence the synthesis th i and d actions ti of f other th cytokines ; Cytokines can work together or against each other 1.3 Cytokines often influence the synthesis and actions of other cytokines (Cascade effect) One cytokine can induce another cytokine cytok ne and so on……. Cytokine C t kin Network 1.4 Cytokine actions may be local and/or systemic 1.5 Cytokines initiate their actions by y binding g to specific membrane receptors on target cells. 1.6 The cellular responses to most cytokines consist of changes in gene expression in target g cells,, resulting g in the expression of new functions in the target cells 2. Functional Categories of cytokines Cytokine families based on their biological function similarity: 2.1 Interleukines 2.2 Interferons 23 C 2.3 Colony l S i l i F Stimulating Factors 2.4 TNF family 2 5 Chemokines 2.5 2.6 Transforming Growth Factors 2.7 Other cytokines y (MIF, ( , c-kit ligand, g , LIF , OsM CNTF etc. 2.1 Interleukins (IL) 1 First seen to be expressed by white blood cells (leukocytes), 1. (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. It has since been found that interleukins are produced by a wide variety y of body y cells. The function of the immune system 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 cells. They promote the development and differentiation of T, B, and hematopoietic cells. 2.2 Interferons (IFNs) Interferons (IFNs) are natural cell-signaling proteins produced by the cells of the immune system in response to challenges such as viruses, parasites i and d tumor cells. ll Interferons assist the immune response p by y inhibiting g viral replication p within host cells, activating immune cells (natural killer cell and macrophages), increasing antigen presentation to T Lymphocytes, and increasing n ng the resistance n of f host cells to viral infection. nf n. There are 3 known classes of interferons; type I, type II and type III. All classes are very important in fighting viral infections. infections Their presence also accounts for some of the host symptoms to infections, such as sore muscles and fever. 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 d thereby th b activate ti t intracellular i t ll l signaling i li pathways th which hi h 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, 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 f to as "colonies." . It w was therefore f possible to add various p u substances u 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 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 (TNF-R) and is part of the extrinsic p pathway y for triggering gg g apoptosis. p p Tumor um necrosis n f factor-alpha p ((TNF-α) NF ) is the m most w well-known n wn member of this class, and sometimes referred to when the term "tumor necrosis factor" is used. Tumor necrosis factor-beta (TNF-β), also known as lymphotoxin is a cytokine that is induced by interleukin 10 [3] 2.5 Chemokines Chemokines (Greek -kinos, movement) are a family of small cytokines, or proteins secreted by cells. Their name is derived fr m th from their ir ability bilit tto induc induce dir directed ct d chemotaxis in nearby responsive cells; they are chemotactic cytokines. Proteins are classified as chemokines according g to shared structural characteristics such as small size (they are all approximately 8-10 kilodaltons in size), and the presence of four cyste cysteine ne res residues dues in conserved locations that are key to forming their 3-dimensional shape. 2.5 Chemokines R Receptors: t 2 28 1 17 2.6 Transforming growth factor (TGF) Transforming T f i growth th factor f t (sometimes ( ti referred f d tto as Tumor T 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, p g brain cells, and keratinocytes, y 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, regeneration, differentiation embryonic development, 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 cells. Selected immunological processes regulated by TGF-β are depicted (MC, mast cell; EO, eosinophil; MO/MΦ, monocyte/macrophage). TGF-β β regulation g of T cell responses TGF-β blocks T cell proliferation by inhibiting IL-2 production via Smad3 and by downregulating the expression of cyclinD2 and E E, CDK4, CDK4 and c-myc. c myc TGF TGF-β β inhibits differentiation of Th1 and Th2 cells through suppressing the expression or function of Tbet/Stat4 and GATA-3/NFAT. Mechanisms involved in TGF-β inhibition of CTL differentiation are not well understood, although inhibition of c-myc and T-bet expression is suggested TGF suggested. TGF-β β induces FoxP3 expression and the generation of Tregs. Tregs TGF-β TGF β also prevents T cell activation-induced cell death (AICD) through inhibiting c-myc-mediated FasL expression and other unknown mechanisms Ming g Li’s work To study the precise function and mechanism of TGF-beta control of immune responses, responses we used a tissue-specific genetargeting technique to i inactivate ti t TGF-beta TGF b t and d TGFTGF beta receptor in various cell types in mice. These studies revealed TGF-beta as a critical regulator of T lymphocyte development, p , homeostasis,, tolerance to self-antigens, and differentiation during the immune responses. responses Ming Li, Sloan Kettering Richard Flavell , Yale 3. Cytokine y Receptors p Immunoglobin domain Receptors in this family has the mm g domain m named m after f the immunoglobulin mm g immunoglobin 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 tryptophanserine-(( 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, family which also is called the hematopoietin receptor family. The class II cytokine receptors possess the conserved CCCC motifs, 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 IL-10 10 receptor is also a member of this group. Tumor necrosis factor receptors p ((TNFRs)) are cytokine y receptors p 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. mammals They each have a 7 transmembrane (7TM) structure 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). 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) y receptor p families is multiple p subunits,, often and the class II cytokine including one subunit that binds specific cytokine molecules and another that mediates signal transduction. Cytokines have numerous functions. 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 p manner. Innate immune systems y 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 (to generate immunity), and to mount stronger attacks k each h time the h pathogen h is encountered. d It is adaptive immunity because the body's immune system prepares itself for future challenges. Main Cytokines in innate immunity TNF I Interleukin-1 l ki 1 Interleukin-12 Type I interferons Interleukin-10 Interferon-γ (IFN-γ): TNF Mediator of acute inflammatory y response p to gram-negative bacteria and other infectious microbes. Major cellular source is activated mononuclear phagocytes (Macrophage stimulated with LPS); Can be membrane protein or released (trimer) Signaling g g by y TNF receptors: p Biological Actions of TNF R Recruitment of f neutrophils h l and d monocytes to sites of infection and activate these cells to eradicate microbes; Large amount cause systemic of TNF can clinical and pathological abonomalities Septic shock (endotoxin shock): vascular collapse. Int l kin 1 (IL-1): Interleukin-1 (IL 1): Mediator M di of f inflammatory i fl response to infectious i f i microbes. M j Major cellular ll l source is i activated ti t d mononuclear l phagocytes; T Two f forms IL 1 and IL-1α d IL-1β IL 1β (30% homologous), IL-1 β need to be cleaved l to be active (ICE:IL-1βconvertingenzyme) Similar effect as TNF Interleukin-12 Produced by activated mononuclear phagocytes and dedritic cells Stimulate IFN production by NK and T lymphoctyes. Enhance E h cytolytic t l ti functions f ti of f activated NK and CTL cells. Is a link between innate and adaptive immunity. Type I interferons: T i t f IFN IFN-α ( 20) and (∼20) d IFN-β Sti l t d by Stimulated b viral i l infection, i f ti mediate di t early l innate immune response to viral infectionsestablishment of “antiviral antiviral state state” Bi l i l Actions: Biological A ti ns: Inhibits viral replication Increase expression of f MHC MH I Stimulate the development of Th1 cells Inhibits the proliferation of many cell time. Interleukin-10: IL10 is an inhibitor of activated macrophages and dedritic cells and is thus involved in the control of innate immune reactions and cellmediated immunity. Produced by activated macrophages. Inhibits the production of IL12; Inhibits the expression of costimulators and MHC II. IL10-/- develop inflammatory bowel disease. Interferon-γ (IFN-γ): IFN-γ is the principal macrophage-activating cytokine that provide the means by which T lymphocytes and NK cells activated macrophages to kill phagocytosed microbes. IFN-γ stimlates expression of MHC I and MHC II molecules l l and d costimulators ti l t on APCs. APC Cytokines mediate and regulate adaptive immunity Interleukin-2 Interleukin-4 Interferon-γ Transforming Growth Factor-β Interleukin-2: IL2 is a growth factor for antigen antigen-stimulated stimulated T T-lymphocytes lymphocytes and is responsible for T cell clonal expansion after antigen recognition. Promote proliferation of antigen-specific antigen specific T cells; Promote the 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 j stimulus for the p production of IgE g 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 inhibite the development of Th2 helper cells Transforming Growth Factor-β (TGF-β): Inhibit the proliferation and action of lymphocytes and other leukocytes Stimulate the differentiation of Tregs and Th17 cells (with IL6). IL6) Signal II Signal I Si Signal l III Th differentiation governed by signal III (cytokines) Revised Th Differentiation Th17 and Treg Cells • Th17 (CD4+, FoxP3-)) – IL-17 is a proinflammatory cytokine – Promotes secretion of pro-inflammatory y (IL-6) ( ) from cytokines fibroblasts, epithelial and endothelial cells. – Th17 cells are critical to anti-bacterial immunity. – Overexpression of IL-17 is associated ass ciated with rheumatoid arthritis, SLE, MS and asthma • T Treg (CD4+, Foxp3 F 3+) – Natural (develop in the thymus) • Prevent effector T cell development in LN – Induced (develop in the periphery) • Develop under the influence of TGF-ß • Inhibit effector T cell function in periphery. Th9 cells ll , Is I it Real? R l? REFERENCES: Veldhoen M et al Transforming growth factor-beta 'reprograms' p g the differentiation of T helper p 2 cells and promotes p an interleukin 9-producing subset. Nature Immunology 9(12): 1341-1346 (2008) Cytokines in hematopoiesis C t ki and Cytokine d disease dis s Cytokine-related Cytokine related diseases Bacterial septic shock endotoxins (cell walls) stimulate production of IL IL-11 and TNF TNF-α α Cancers of lymphoid system system- overproduction of cytokines such as IL-6 (B-cell) or IL-5 (Hodgkin’ss disease) or IL (Hodgkin IL-2 2 (adult T T-cell cell leukemia) Chagas’ disease (parasitic)- suppression of α-subunit α subunit of IL IL-2 2 receptor Cytokine y therapies p Interferons IFN-α- certain types of tumors IFN-β- multiple sclerosis th s are antiviral these ntivi l IFN-γ- 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 (t necrosis i factors) f t ) TNF-α and β In some cases inhibit proliferation of tumor cells ll but b t nott normall cells ll M d May damage vascular l endothelial d th li l cells ll in i tumors, thus inhibiting blood supply t the to th tumor t Cytokine related technology ELISA and FACS ((Cytokine y detection)) Recombinant protein (gene engineering, P d Production i of f large l amount of f cytokines) ki )