《细胞因子与受体》PPT课件

1,细胞因子,Cytokine,一、细胞因子导论二、细胞因子参与的信号通路三、几个重要细胞因子及其信号通路,2,目录,细胞因子在信号通路中的位置细胞因子的定义细胞因子的产生细胞因子的命名和种类细胞因子发挥作用的方式细胞因子的共同特点细胞因子的生物学效应细胞因子受体,3,一、细胞因子导论,4,细胞因子在信号通路中的位置：靶基因或者胞外信号,5,细胞因子作为胞外信号，与激素和神经递质并列,内分泌系统免疫系统神经系统,6,由活化的免疫细胞和某些非免疫细胞经刺激而合成、分泌的一类小分子多肽，具有调节细胞生长、分化、成熟、调节免疫应答、参与炎症反应、促进伤口愈合以及肿瘤消长等功能。,免疫球蛋白(抗体)、补体不包括在细胞因子之列。,细胞因子的定义,1.活化的免疫细胞2.基质细胞:3.某些肿瘤细胞,7,细胞因子的产生,血管内皮细胞、上皮细胞、神经胶质细胞、成纤维细胞,细胞因子相当于这些细胞中信号通路的靶基因和最终产物。,NK细胞，naturalkillercell，自然杀伤细胞,嗜碱性细胞在结缔组织和粘膜上皮内时，称肥大细胞,（一）根据产生细胞因子的细胞种类不同分类淋巴因子（lymphokine)单核因子（monokine）非淋巴细胞、非单核-巨噬细胞产生的细胞因子（二）根据细胞因子主要的功能不同分类1.白细胞介素（interleukin,IL)2.干扰素（interferon,IFN)3.集落刺激因子（colonystimulatingfactor,CSF)4.肿瘤坏死因子（tumornecrosisfactor,TNF)5.趋化因子家族（chemokinefamily)6.生长因子家族（growthfactorfamily,GF),8,细胞因子的命名和种类,9,自分泌autocrine,内分泌endocrine,血液循环,远距离作用,旁分泌paracrine,作用于比邻细胞,细胞因子发挥作用的方式：旁分泌和自分泌为主,作用于分泌细胞自身,1.低分子量2.多源性和多向性（产生）3.短时自限性4.非特异性5.高亲和力和高效性6.多效性和重叠性7.协同性、拮抗性和网络性8.双重性,10,细胞因子的共同特点,分泌型小分子糖蛋白（MW60kD),单链或双链，三聚体（TNF）,（1）有利：免疫调节、促进造血、抗感染、抗肿瘤（2）有害：炎症、休克、发热、自身免疫病、肿瘤,通过与其受体结合而发挥效应，量微而作用强,无前体储存，刺激才合成，无刺激即停止，产物迅速被分解,（1）一种细胞可分泌多种细胞因子（2）几种不同的细胞可产生一种或几种相同的细胞因子,一种细胞因子可以作用于不同的细胞，无抗原特异性和MHC限制性,11,肥大细胞,胸腺细胞,B,IL-4,多效性pleiotropy,活化、增殖、分化,增殖,增殖,12,13,网络性,14,Biologicactivity,1.Takepartininnateimmunity2.Takepartinadaptiveimmunity3.Stimulatehematopoiesis4.Mediateinflammation,15,先天性免疫,浆细胞体液免疫,APC,Th：CD4+,Tc：CD8+,Th1细胞免疫,Th2,获得性免疫,血细胞,免疫细胞（白细胞）,APC：antigen-presentingcell,16,IFN-a的抗病毒作用,病毒,病毒复制,抑制病毒复制,信号转导,IFN-a,IFN-诱导蛋白,诱导刺激,胞核,胞核,1.Takepartininnateimmunity,17,APC,antigen-presentingcell;IRF,IFN-regulatoryfactor;NK,naturalkiller;TCR,T-cellreceptor;Bcl-6,B-celllymphoma6,2.Takepartinadaptiveimmunity,定型细胞,18,Th1-Th2分泌细胞因子的相互调节及其效应,B细胞,IgG2a,Tc细胞活化,巨噬细胞活化,B细胞,IgM，IgG1，IgA，IgE,肥大细胞生长,嗜酸性粒细胞生长与分化,B细胞，巨噬细胞,Th2细胞，肥大细胞,IL-12,IL-4,IL-10,IFN-g,Th1,IFN-g,IL-12,IL-4,IL-110,IL-13,IL-2,IFN-g,TNF-b,IL-12,IL-3IL-4,Th2,IL-10,IL-5,IL-4,19,20,3.Stimulatehematopoiesis,21,ModulationofinvivoinflammationbytheD6chemokinereceptordecoy.,PMA：Phorbolester(佛波酯)T：TlymphocytesE：neutrophilsM：mastcells,4.Mediateinflammation,22,23,Cytokinereceptors,Membrane-bindingcytokinereceptors(1)Immunoglobulinfamily（IGSF）(2)TypeIcytokinereceptorfamily（EPOR）(3)TypeIIcytokinereceptorfamily（INFR）(4)TypeIIIcytokinereceptorfamily（NGFR，TNFR）(5)Chemokinereceptorfamily（GPCR）2.Solublecytokinereceptors,EPO：erythropoietinCRF：cytokinereceptorfamily,CRF,24,25,Membrane-bindingcytokinereceptors,TKCR(CRF),ligand-receptor+TK,NRTK：Jak,EPOR,INFR,TNFR,ChemokineReceptor,26,ReceptorofGrowthfactors（RTK）,27,28,commonsubunits（共用信号链）,Commongammachain：CD132（gene：IL2RG）Commonbetachaingp130意义：不同的细胞因子，相同的信号传导和生物学活性。,29,gp130,30,31,2.SolublecytokinereceptorsCompetitiveinhibitionTransporterofcytokineIL-1、IL-2、IL-4、IL-5、IL-6、IL-7、IL-8G-CSF、GM-CSF、IFN、TNF,JAK-STATSMAPK（ERK、JNK、p38）NF-kBApoptosisGPCR,32,二、细胞因子参与的信号通路,33,ModelofJAK-STATsignaling,JAK:justanotherkinase/januskinaseSTAT:SignaltransducersandactivatorsoftranscriptionY：tyrosinephosphorylatedS：serinephosphorylatedPrl,prolactin,RTK,NRTK,34,35,PRO：Prolactin，泌乳素Epo：erythropoietin，促红素Tpo：thrombopoietin，血小板生成素,36,37,MAPKsignalingcascades,ras,ras,38,NF-B,nuclearfactorkappa-light-chain-enhancerofactivatedBcells,39,DiscoveryofNF-B,DavidBaltimore(NobelPrize,1975),3geneclusterheavychain:1lightchain:2、,40,ThestepsinimmunoglobulingenerearrangementatwhichcellscanbelostThedevelopmentalprogramusuallyrearrangestheheavy-chain(H-chain)locusfirstandthenthelight-chain(L-chain)loci.Cellsareallowedtoprogresstothenextstagewhenaproductiverearrangementhasbeenachieved.Eachrearrangementhasaboutaoneinthreechanceofbeingsuccessful,butifthefirstattemptisnonproductive,developmentissuspendedandthereisachanceforoneormorefurtherattempts.Thescopeforrepeatedrearrangementsisgreateratthelight-chainloci,sothatfewercellsarelostbetweenthepre-BandimmatureBcellstagesthaninthepro-Btopre-Btransition.,41,42,SchematicrepresentationofmembersoftheRel/NF-B,DNAbindingnuclearlocalizationsubunitdimerization,LZ,leucinezipper;TD,transactivationdomain;GRR,glycine-richregion;PEST:proline(P),glutamicacid(E),serine(S)andthreonine(T);DD,deathdomain;,ConstitutiveSelective,(p65),43,IKKphosphorylationsites:degradation,SchematicrepresentationofmembersoftheIBfamiliesofproteins,Maskthenuclearlocalizationsignals(NLS),44,Oneofthemostcommonprotein-proteininteractionmotifsinnature.33-residue,twoalphahelices,AnkyrinRepeat,repressorsHomodimersofp50andp52activatorsHeterodimerswithRelA,RelB,orc-RelHomodimersofp50andp52+Bcl-3,45,46,Figure3ModelofdifferentNF-Bsignallingpathways,secondarylymphoidorganogenesismaturationofB-cellsadaptivehumoralimmunity,ImmuneresponsesInflammationPromotingcellsurvival,immuneresponsesinflammatoryresponses,NEMO(IKKgamma):NF-BessentialmodulatorNIK:NF-B-inducingkinase,(IKKgamma),(NF-B-inducingkinase),1.INFSignaling2.ChemokineSignaling3.TNFSignaling4.ILSignaling,47,三、几个重要细胞因子及其信号通路,Interferonsplayanimportantroleinthefirstlineofdefenseagainstviralinfections.Theyarepartofthenon-specificimmunesystemandareinducedatanearlystageinviralinfectionbeforethespecificimmunesystemhashadtimetorespond.Interferonsaremadebycellsinresponsetoanappropriatestimulus,andarereleasedintothesurroundingmedium.Theythenbindtoreceptorsontargetcellsandinducetranscriptionofapproximately20-30genesinthetargetcells,andthisresultsinananti-viralstateinthetargetcells.,48,1.INFSignaling,49,TypesofInterferon,LPS:Lipopolysaccharide,脂多糖,50,IFN-a的抗病毒作用,病毒,病毒复制,抑制病毒复制,信号转导,IFN-a,IFN-诱导蛋白,诱导刺激,胞核,胞核,ViralinfectionandreplicationintroducesssRNA,dsRNAandDNA:RNAhybridbyproducts.TLRsendosomesRNAhelicasescytoplasmphosphorylationofTFtypeIinterferonexpressionSecreteinterferon,INFandINFRbindinductionofgenes：Cytokineschemokinesapoptosis-relatedgenes,51,Interferonpathway：Secretion、signalingandfunction,pDC,pDC：plasmacytoiddendriticcell浆细胞样树突状细胞TLR:toll-likereceptorsRNAhelicases：RIG-1andMda-5IRF：interferonregulatoryfactors3,5,7and9INFAR：interferonreceptors,Interferon-induciblegenes：20-30proteinsCytokinesChemokinesapoptosis-relatedgenes,Theseactivitiestargetviralproteinsynthesis,butalsoresultininhibitionofhostproteinsynthesis.Itisimportantthattheseproteinsareonlymadeandactivatedwhenneeded.,52,INFfunction,R,（medicine）,indirectly,directly,directly,53,TherapeuticUsesOfInterferons,54,常染色体隐性遗传性脑病，小头畸形，脑钙化,吸引白细胞移行到感染部位。多肽前体（包括信号肽）。四个位置保守的半胱氨酸残基形成两对双硫键,55,2.ChemokineSignaling,56,四类趋化因子,GPCR四组，共19种。CXCR：6种CCR：11种XCR：1种CX3CR：1种,57,四类趋化因子受体,58,趋化因子及其受体,59,趋化因子的靶细胞,60,61,62,1RegulationofAC2RegulationofPLCpathways3Ionchannelregulation4RegulationofMAPKpathways5RegulationofPLA2activity6cADPR,63,IntracellularsignallingpathwaysactivatedbyCCR,正常：造血作用、淋巴组织发育、炎症反应、白细胞迁移、过敏、伤口修复、新血管生成、癌症发生和肿瘤迁移等。异常：多发性硬化症、类风湿关节炎、动脉硬化、哮喘和移植排斥等。,64,趋化因子的生理意义,65,趋化因子参与的疾病,牛皮癣,结节病,血管球性肾炎,骨关节炎,急性呼吸窘迫,哮喘,肺炎,风湿性关节炎,炎性肠病,脑膜炎,动脉粥样硬化,66,Figure1Diseasetargetsofchemokinereceptorsandligands,BiochemicalSocietyTBiochem.Soc.Trans.(2004)32,366-377,过敏,特应性皮炎,肿瘤迁移,HIVlysesCD4+T4cellsspecifically,causingtheprofoundimmuno-suppressionthatisthehallmarkofAIDS.,67,Chemokinesandchemokinereceptors:roleinHIVinfection,CD4+T4helpercellsNaturalKillercellsCD8+KillerTcellsMacrophagesDendriticcellsCellsofthenervoussystem(oligodendrocytes,astrocytes,neurones,glialcellsandbrainmacrophages),68,CellsthatareinfectedbyHIV,Theouterdomainofgp120bindstotheCD4antigen.Thisleadstoaconformationalchangeingp120andaco-receptorbindingsiteisexposed.Thisregionofgp120bindstothechemokinereceptor.Bindingtothechemokinereceptorallowsanotherconformationalchangetooccursothatregionsofthegp41HIVproteininteracttoformafusiondomainthatallowstheviralandcellmembranetofuse.Asaresulttheviralcoreentersthecytoplasm.,69,ChemokinereceptorhelpHIVtoenteracell,Chemokinereceptorsareinvolved,inassociationwithCD4antigen,ininfectionbyHIV(left).Thechemokinecanblockattachmentofthevirustoitsreceptors(middle).MutationsinthechemokinereceptorcanleadtoresistancetoHIVinfection(right),70,ChemokinesresisttoHIVinfection,EntryofHIVviathemucosalrouteandtransitviadendriticcellstothelymphnodes,71,72,regulateimmunecellsinduceapoptoticcelldeathinduceinflammationinhibittumorigenesisinhibitviralreplication,73,3.TNFSignaling,74,TNF,75,TNFR超家族成员的功能,76,77,CD95(orFas)DR4DR5TNFR1DR3(DR6?),78,Deathreceptors(DR),(FADD),(TRADD),DRs,TNFR,ReceptorwithoutDD,79,127aa.6antiparallel,amphipathicalpha-helices,80,Deathdomain(DD),FasDD,FADD：Fas-associateddeathdomainprotein,81,Adaptor,1.FADD2.TRADD,caspases8and10（apoptosis-initiatingproteases）,RIP1（DD-containingkinase）TRAF2（E3ubiquitinligases）cIAPs（cellularinhibitorofapoptosisproteins）,TRADD：TNFreceptorassociatedDD,TRAF2：TNFreceptorassociatedfactor2,RIP1：receptor-interactingprotein-1,82,83,FADD-mediatedDRsignaling,DISC：death-inducingsignalingcomplex,autocatalyticprocessing,Tcells,Bcells,Bcl-2familyprotein,84,TRADD-mediatedDRsignaling,1.Proinflammatorycytokines2.Chemokines3.Antiapoptoticfactors（cIAPs,c-FLIP）,1.Proliferation2.Differentiation3.Inflammation4.Apoptosis.,polyubiquitinationofRIP1,cIAPs,85,ComplexI,ComplexII,Cross-talkbetweenDRsignalingadaptors,86,ToDie?OrTolive?,ModelofTNFR1-MediatedApoptosis,IfNF-kBactivationtrigg