1、Section IV Effector Mechanisms of Immune ResponsesChapter 11 CytokinesqNomenclature:1.Based on their cellular sources:Monocyte-Monokine;Lymphocyte-Lymphokine;2.Because many cytokines are made by leukocytes and act on other leukocytes,they are also called interleukines.3.In this book,we use term cyto
2、kine,which does not imply restricted cellular sources or biologic activities.Nomenclature:General Properties of Cytokines:1.Cytokine secretion is a brief,self-limited event.1)Cytokines are not usually stored as performed molecules.2)When cell was activated,the synthesis of cytokines is initiated.2 C
3、ytokines can act in three different manners Autocrine Cytokine binds to receptor on cell that secreted it.2.ParacrineCytokine binds to receptors on near by cells3.EndocrineCytokine binds cells in distant parts of the body3 Cytokine Actions Pleiotropy Act on more than one cell typeRedundancyMore than
4、 one cytokine can do the same thing(IL-2,IL-4,IL-5)SynergyTwo or more cytokines cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately(IFN-g g and TNF)AntagonismTwo or more cytokines work against each other(IL-10 and IFN-
5、g g)4.Cytokines make functions in binding to receptorKd:10-10-10-125.External signals regulate the expression of cytokine receptor.6.Cytokines can change the gene expression in target cells.1.Mediators and regulators of innate immunity:Secreted by mononuclear phagocytes,these members of cytokines ca
6、n stimulate the early inflammations.2.Mediators and regulators of adaptive immunity.Secreted by T lymphocytes,some of them regulate the proliferation and differentiation of lymphocytes.Recruit,activate,regulate specialized effector cells.3.Stimulators of hematopoiesis.Are produced by bone borrow str
7、omal cells,stimulate the growth and differentiation of immature leukocytes.Table 11-1.Comparative Features of the Cytokines of Innate and Adaptive ImmunityFeaturesInnate immunityAdaptive immunityExamplesTNF-,IL-1,IL-12,IFN-*IL-2,IL-4,IL-5,IFN-*Major cell sourceMacrophages,NK cellsT lymphocytesPrinci
8、pal physiologic functionsMediators of innate immunity and inflammation(local and systemic)Adaptive immunity:regulation of lymphocyte growth and differentiation;activation of effector cells(macrophages,eosinophils,mast cells)StimuliLPS(endotoxin),bacterial peptidoglycans,viral RNA,T cell-derived cyto
9、kines(IFN-)Protein antigensAmounts produced Local or systemic effectsMay be high;detectable in serum BothGenerally low;usually undetectable in serum Usually local onlyRoles in diseaseSystemic diseases(e.g.,septic shock)Local tissue injury(e.g.,granulomatous inflammation)Inhibitors of synthesisCortic
10、osteroidsCyclosporine,FK-506qCytokine Receptors Cytokine Receptor:consist of one or more transmembrane proteins,the classification of cytokine receptors is based on structural.Cytokine receptors are divided into five families:1)Class I cytokine receptor family(hemopoietin receptors)Binds most of the
11、 cytokines in the immune and hematopoietin systems2)Class II cytokine receptor family3)Immunoglobulin superfamily receptors4)TNF receptor family5)Chemokine receptor familyFive families of Cytokine Receptor Structure1.Type 1 cytokine receptors1)Two Conserved pairs of cysteine residues2)Membrane proxi
12、mal WSXWS sequence3)Unique ligand binding and others for signal-transducing chains.Among type 1 cytokine receptor,three subtype family exit:2.Type II cytokine receptors1)With conserved cysteins2)Without WSXWS motif3.Ig superfamily family.4.TNF recptorsWith conserved cysteine-rich extracellular domai
13、ns.5.Seven-transmembrane a a helical receptors1)Also called serpentine receptors2)Mediate rapid and transient responses to a family of cytokines.Cytokines in ImmunityqCytokines that mediate and regulate innate immunityCytokineSizePrincipal cell sourcePrincipal cell targets and biologic effectsTumor
14、necrosis factor(TNF)17 kD;51-kD homotrimerMacrophages,T cellsEndothelial cells:activation(inflammation,coagulation)Neutrophils:activationHypothalamus:feverLiver:synthesis of acute-phase proteinsMuscle,fat:catabolism(cachexia)（恶病质）（恶病质）Many cell types:apoptosisInterleukin-1(IL-1)17 kD mature form;33-
15、kD precursorsMacrophages,endothelial cells,some epithelial cellsEndothelial cells:activation(inflammation,coagulation)Hypothalamus:feverLiver:synthesis of acute-phase proteinsChemokines(see Table 11-4)8-12 kDMacrophages,endothelial cells,T cells,fibroblasts,plateletsLeukocytes:chemotaxis,activation;
16、migration into tissuesInterleukin-12(IL-12)Heterodimer of 35-kD+40-kD subunitsMacrophages,dendritic cellsT cells:TH1 differentiationNK cells and T cells:IFN-synthesis,increased cytolytic activityType I IFNs(IFN-,IFN-)IFN-:15-21 kDIFN-:20-25 kDIFN-:macrophagesIFN-:fibroblastsAll cells:antiviral state
17、,increased class I MHC expressionNK cells:activationInterleukin-10(IL-10)Homodimer of 34-40 kD;18-kD subunitsMacrophages,T cells(mainly TH2)Macrophages,dendritic cells:inhibition of IL-12 production and expression of costimulators and class II MHC moleculesInterleukin-6(IL-6)19-26 kDMacrophages,endo
18、thelial cells,T cellsLiver:synthesis of acute-phase proteins B cells:proliferation of antibody-producing cellsInterleukin-15(IL-15)13 kDMacrophages,othersNK cells:proliferation T cells:proliferation(memory CD8+cells)Interleukin-18(IL-18)17 kDMacrophagesNK cells and T cells:IFN-synthesis一一Tumor Necro
19、sis Factor(TNF):1.Definition:TNF-a,a,a substance present in the serum of animals with bacterial endotoxin that caused the necrosis of tumors in vivo.2.Production,Structure,Receptors Production:Product cell:mononuclear phagocytes,NK cells,mast cells.Stimulus:LPS,gram-negative bacteria which release L
20、PS.StructureMonomer:17kDHomotrimer:51kDReceptor:1.Two distinct TNF receptor:type I and type II2.K d:10-9 for TNF-RI and 10-10 for TNF-RII.3.Two types of receptor are presented on all cell types.3.Signal 1)TNF-RI:TRADD binding TRAF and RIP,leading to new gene expression2)TNF-RI:recruitment a protein,
21、called TNF receptor associated factors(TRAFs),TRAF then bind to FADD,leading to apoptosis.4.Biologic Actions1)Stimulate the recruitment of neutrophils and monocytes to sites of infection and to activate these cells to eradicate microbes.i.TNF stimulates cytokines to enhance the leukocyte recruitment
22、.ii.TNF causes cell to express adhesion molecules to make leukocyte adhere to the endothelial cell.4.Biologic Actions2)In severe infections,TNF is produced in large amounts and causes systemic clinical abnormalities.i.TNF is an endogenous pyrogen.ii.TNF constitutes the acute-phase response to inflam
23、matory stimuli.iii.TNF production causes wasting of muscle and fat cells.iv.If high quantities of TNF are produced,resulted in shock.v.TNF causes intravascular thrombosis.二二IL-11.Character:similar to TNF,a mediator of the host inflammatory response to infections and other inflammatory stimuli.2.Prod
24、uction,Structure,Receptor Production:activated mononuclear phagocytes also:neutrophils,epithelial cells and endothelial cells Structure:IL-1a a and IL-1b b.Receptor:type I receptor on all cell surface.type II receptor on B cell,a decoy.IL-1IL-1ReceptorSignal:IL-1 binding to IL-1 receptor leads to th
25、e activation of IRAK and ultimately NFk kB and AP-1.4.Biologic Actions1)At low concentration,IL-1 mediate the local inflammation2)At high concentration,IL-1 shares with TNF the ability to cause fever.3)Doesnt induce apoptotic death.4)Doesnt cause the pathophysiologic changes of septic shock.5)Doesnt
26、 make tumor cell negrosis.三三Chemokines:C5aC5a和细菌代谢产物和细菌代谢产物细胞因子细胞因子（IL-8)Definition:stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues.Structure,production,ReceptorsStructure:according to the location of N-terminal cysteine residues.I、CXC（a a）趋化因子：）趋化因子：C
27、XCCCII、CC（b b）趋化因子：）趋化因子：CCCCIII、C（g g）趋化因子：）趋化因子：CC IV、CX3C（）趋化因子：）趋化因子：CXXXCCCProduction:CC and CXC:are produced by leukocytes,endothelial cells,epithelial cells and fibroblasts or T cells.Some:are induced by microbes and by inflammatory cytokines.Others:are produced constitutively without any inf
28、lammatory stimulus.Receptor:1.At least 10 distinct receptors for CC chemokines and 6 for CXC chemokines.2.Are expressed on leukocytes.Chemokines and receptorBiologic Actions:1.Chemokines recruit the cells of host defense to sites of infection.T：CCR7;DC：CCR7;B：CCR7、CXCR5;TH：CXCR5T区区HEV：CCL21;B滤泡区滤泡区H
29、EV：CXCL13T与与DC在在T区作用，分化效区作用，分化效应细胞应细胞;TH与与B在在B区作用，协助区作用，协助Ab产生和类别转换。产生和类别转换。2.Regulate the lymphocytes to move to different zones.四四IL-12Definition:a principle mediator of the early innate immune response and is a key inducer of cell-mediated immunity.Structure,production,ReceptorsStructure:a disulf
30、ide linked heterodimer 35-KD and 40-KD.Production:activated mononuclear phagocytes and dendritic cells.This production can be induced by helper T cells and NK cells.Receptor:SignalJAK/STAT Pathway.JAK:Janus kinasesSTAT:signal transducers and activators of transcription.Signal:through a JAK/STAT path
31、way，JAK1-STAT4.JAK/STATInvolved cytokines*Phenotype of knockout miceSTAT1IFN-/,IFN-Defect in innate immunity;no reponse to IFNsSTAT2IFN-/Defective immunity to virusesSTAT3IL-6,IL-10Embryonic lethalSTAT4IL-12Defect in TH1 development,IFN-g productionSTAT5aProlactinLactation defectSTAT5bGrowth hormone
32、DwarfismSTAT5a andSTAT5bIL-2,IL-7,IL-9(in additionto above)Lactation defect,dwarfism,and defective T cellproliferation in response to IL-2STAT6IL-4Defect in TH2 development,IL-4-dependent Ig isotypesJAK1IFN-/,IFN-,cytokines using c and gp130(e.g.,IL-2,IL-4,IL-6)Perinatal lethal;defective innate immu
33、nity,possible defect in neuronal viabilityJAK2Epo,IL-3,IFN-Embryonic lethal,hematopoietic failureJAK3Cytokines using c chain(IL-7,IL-2,IL-4)Defect in T cell maturationTyk2IFN-/,IFN-,IL-12,IL-10,othersDefective IL-12 response of NK cells,defective immunity to virusesCytokines involved in JAK/STAT pat
34、hwayBiologic Actions:1.Stimulate the production of IFN-g.g.MicrobesMacrophage responseIL-12IFN-g gMacrophage activationKilling of microbes2.Differentiation of CD4+helper T cells into IFN-g g producing TH1 cells.3.Enhances the CTLs.五五Type I Interferons(IFNs)Definition:the ability of these cytokines t
35、o interfere with viral infection.Structure,Production,ReceptorsStructure:IFN-a a and IFN-b.b.IFN-a,a,a family of 20 structurally related polypeptides,each encoded by a separate gene.IFN-b,b,is a single protein.Production:stimulated by viral infection,specifically double-stranded RNA.IFN-a,a,produced
36、 by mononuclear phagocytes,sometimes called leukocyte interferon.IFN-b,b,produced by many cells,such as fibroblast,also called fibroblast interferon.Receptor:IFN-a a and IFN-b b bind to the same cell surface receptor and induce similar biologic responses.Biologic Actions1.Inhibit viral replication.1
37、)2,5 oligoadenylate synthetase2.Increases expression of MHC I molecules.3.Stimulates the development of Th1 cells in humans.4.In vitro,inhibits the proliferation of many cell types.六六Interleukin-10Definition:is an inhibitor of activated macrophages and dendritic cells.Production,Structure,ReceptorsP
38、roduction:mainly by activated macrophages.Structure:a four-a a-helical globular domain structure.Receptor:type II cytokine receptor.Biologic Actions:1.IL-10 inhibits the production of IL-12 by activated macrophages and dendritic cells.2.IL-10 inhibits the expression of costimulators and class II MHC
39、 molecules on macrophages and dendritic cells.七七Biological activity of IL-6Biological activity of IL-15Roles of Cytokines in Innate Immunity and Inflammation1.For extra cellular bacteria,LPS stimulates macrophages produce TNF,IL-1,chemokines.1)TNF,IL-1 promote stable attachment of blood neutrophils
40、and monocytes to the infection site.2)Chemokines stimulate leukocytes to the infection.Roles of Cytokines in Innate Immunity and Inflammation2.For intracellular bacteria,Macrophages also secrete IL-12,which can induce the local production of IFN-g g from NK and T cells.3.IL-12 also stimulates the su
41、bsequent adaptive immune response and directs it toward Th1 cells.4.In viral infection,4.1 Type I IFNs are secreted by infected cells and macrophages and function to inhibit viral replication.4.2 IL-15 stimulate expansion of NK cells4.3 IL-12 enhances the cytolytic activity of NK cells.qCytokines in
42、 Adaptive ImmunityTable 11-4.Cytokines of Adaptive ImmunityCytokineSizePrincipal cell sourcePrincipal cell targets and biologic effectsInterleukin-2(IL-2)14-17 kDT cellsT cells:proliferation,increased cytokine synthesis;potentiates Fas-mediated apoptosisNK cells:proliferation,activationB cells:proli
43、feration,antibody synthesis(in vitro)Interleukin-4(IL-4)18 kDCD4+T cells(TH2),mast cellsB cells:isotype switching to IgE T cells:TH2 differentiation,proliferation Macrophages:inhibition of IFN-mediated activationMast cells:proliferation(in vitro)Interleukin-5(IL-5)45-50 kD;homodimer of 20-kD subunit
44、sCD4+T cells(TH2)Eosinophils:activation,increased productionB cells:proliferation,IgA productionInterferon-(IFN-)50 kD(glycosylated);homodimer of 21-to 24-kD subunitsT cells(TH1,CD8+T cells),NK cellsMacrophages:activation(increased microbicidal functions)B cells:isotype switching to opsonizing and c
45、omplement-fixing IgG subclassesT cells:TH1 differentiationVarious cells:increased expression of class I and class II MHC molecules,increased antigen processing and presentation to T cellsTransforming growth factor-(TGF-)25 kD;homodimer of 12.5-kD subunitsT cells,macrophages,other cell typesT cells:i
46、nhibition of proliferation and effector functionsB cells:inhibition of proliferation;IgA production Macrophages:inhibitionLymphotoxin(LT)21-24 kD;secreted as homotrimer or associated with LT2 on the cell membraneT cellsRecruitment and activation of neutrophils Lymphoid organogenesisInterleukin-13(IL
47、-13)15 kDCD4+T cells(TH2)B cells:isotype switching to IgEEpithelial cells:increased mucus productionMacrophages:inhibition一一 IL-2:1.Definition:a growth factor for antigen-stimulated T lymphocytes and is responsible for T cell clonal expansion after antigen recognition.2.Production,Structure,Receptor
48、s Production:produced by CD4+T lymphocytes and with peak secretion occurring about 8-12 hours after activation.Structure:Receptors:The expression of functional IL-2 receptors is enhanced.IL-2 receptor1)1)a,b,g a,b,g chain noncovalently associated.2)The a a and b b chains are involved in cytokine bin
49、ding,the b b and g g are involved in signal transduction.3)IL-2Ra a is a 55-kD poplypeptide and appears on activated T cells.4)IL-2Rb b is expressed at low levels on resting T cells associated with a polypeptide g g chain.IL-2 receptor complex binding IL-2 is changed during the process of T activati
50、on.Signal:Biologic Actions:1.Is responsible for the proliferation of the antigen specific cells.1.Is responsible for the proliferation of the antigen specific cells.2.Promotes the proliferation and differentiation of other immune cells.3.IL-2 serves to terminate immune responses by stimulating the d
