醫(yī)學免疫學教學課件：06-細胞因子Cytokines and their receptors

CytokinesandtheirreceptorsIntroductiontocytokinesCategoriesofCKsBiologicalfunctionofCKsCytokinereceptorClinicalapplicationofcytokinesIntroductiontocytokinesCytokine(CK)

Cytokinesaresmallsolubleproteinsthatmediateimmuneandinflammatoryreactionsandareresponsibleforcommunicationsbetweenleukocytesandothercells.Cytokinesworkbybindingtoatargetcell.Therefore,foracytokinetohaveaneffect,twothingshavetooccur:ThecytokineneedstobepresentthereThetargetcellneedstohaveareceptoronitssurfaceTherefore,regulationcanoccurateitherstep.TheresearchofCKcanhelpustoclarifythemechanismofimmuneresponsesatthemolecularlevelandtounderstandthepathogenesisofsomediseases.ManyCKsandtheirantagonistscanbeusedinthetreatmentofmanydiseases(suchascancer,infection,autoimmunediseases)andtopromotehemopoiesis,etc.

Accordingtotheirsource1)Monokine2)Lymphokine

Accordingtotheirfunction1)Colonystimulatingfactor2)Interleukin3)Interferon4)Tumornecrosisfactor5)Growthfactor6)ChemokineGeneralpropertiesofCKsSmallproteins(MW:approx.8-30KD)Extremelypotent,actingat10-9~10-15MTheproductionistransientandtightlyregulatedAutocrine,paracrineorendocrineCytokineactions:Pleiotropy,Redundancy,SynergyandAntagonismMannerofaction1)Autocrine:IL-2ThTh2)Paracrine:IL-12DCTh3)Endocrine:IL-1,TNF-

Undercertaincircumstances(e.g.septicshock),largeamountsofCKs(suchasTNF-)areproduced,theymaybeactivedistantfromtheirsiteofsecretion.Cytokineactions1)Pleiotropy

Actsonmorethanonecelltype(IL-4)2)Redundancy

Morethanonecytokinehavethesameaction(IL-2,IL-7,IL-15)3)Synergy

Twoormorecytokinescooperatetoproduceaneffectthatisdifferentorgreaterthanthecombinedeffectofthetwocytokineswhenfunctioningseparately(IL-4andIL-5)4)Antagonism

Twoormorecytokinesworkagainsteachother(IL-4andIFN-)Thecytokinenetwork:Manycytokineshavemultiplefunctionsandapparentredundancyofactionsformingacomplexcommunicationnetwork.CategoriesofCKsCKsareclassifiedinto6functionalcategoriesInterleukin(IL)Interferon(IFN)Tumornecrosisfactor(TNF)Colonystimulatingfactor(CSF)ChemokineGrowthfactor(GF)Interleukin,ILCytokinesproducedbyleukocytesandactonleukocytesIL-1~35IL-2,IL-7,IL-9,IL-15constitutecommonchainfamilyIL-4,IL-5,IL-6,IL-13(Th2type)IL-8(belongstochemokinefamily)IL-10(Trtype)IL-11(stimulatorofplatelets)IL-12(DC,macrophages,directsTh1)Interferon,IFNIFNsaremediatorsoftheinnateimmuneresponseandTh1/CTLresponses.Groups

TypeIIFN:IFN-andIFN-Themajorsourceisleukocytes(PDC),fibroblastsHelppreventthespreadofvirustouninfectedcells.

TypeIIIFN:IFN-

IFN-isproducedbyactivatedTcellsandNKcells.Itsmainfunctionisimmuneregulation.Tumornecrosisfactor,TNFTNFwasoriginallyidentified(andwassonamed)asasubstancethatcancausethenecrosisoftumorsinvivo.TNF-andTNF-TNF-isproducedbyLPS-stimulatedmononuclearphagocytesandactivatedTcells.Involvedininflammation.TNF-isalsotermedlymphotoxin(LT),andisproducedmainlybyactivatedTcells.Colony-stimulatingfactors,CSFStimulatesthedifferentiationandexpansionofbonemarrowprogenitorcells.Itisassayedbyitsabilitytostimulatetheformationofcellcoloniesinculture.IncludesIL-3,CSF(G-CSF,M-CSF,GM-CSF),SCF,EPO,TPO,etc.Chemokines(chemotacticcytokines)ChemokinesarealargefamilyofstructurallyhomologousCKsthatstimulatemovementandregulatethemigrationofleukocytesfromthebloodtotissuesandwithintissues.About50differentmembers.Subfamilies:CXC,CC,C,CX3C,basedonstructuralcharacteristics(cysteineresidues).IL-8CXCneutrophilsMCP-1CCmonocyteLymphotactinClymphocyteFractalkineCX3ClymphocyteChemokinesSubfamilyTargetCellsStepsinvolvedinneutrophilchemotaxisandtransendothelialmigrationshowingreversiblebindingfollowedbyactivation,adherence,andmovementbetweentheendothelialcellsformingthewallofthebloodvessel.Growthfactors,GFPromotetheproliferationanddifferentiationofcells.IncludeTGF-,EGF,VEGF,FGF,NGF,PDGF,etc.BiologicfunctionsofCKs(1)Anti-bacteria:IL-1,TNF,IL-6,IL-8andIL-12Anti-virus:typeI,IIIFNMediationandregulationofadaptiveimmunity:*Stimulatingtheproliferationoflymphocytes:

IL-2,IL-7,IL-15.*Stimulatingthedevelopmentoflymphocytes:IL-12,IFN-,IL-4.*Enhancingtheactivityofeffectorcells:IFN-,IL-2,IL-6.*Inhibitingimmuneresponse:TGF-,IL-10CytokinesecretionandbiologicalactivitiesofTh1andTh2subsetsType1Type2IL-2IFN-γTNFIL-4IL-5IL-10Cell-mediatedImmuneresponse(intracellularorganisms)Humoralresponse(parasites,extracellularmicrobes)TcellThefunctionsofTh1andTh2cells.FunctionsOfCytokinesThedifferentiationofna?veCD4+ThcellsintoTh1andTh2effectorcells.EffectorandregulatoryCD4+Tcellsubsetsinvolvedinachievingthebalancebetweentheanti-infectiveimmuneresponseandhostpathology.Th17andTregCellsTh17(CD4+,FoxP3-)IL-17isapro-inflammatorycytokinePromotessecretionofpro-inflammatorycytokines(IL-6)fromfibroblasts,epithelialandendothelialcells.Th17cellsarecriticaltoanti-bacterialimmunity.OverexpressionofIL-17isassociatedwithrheumatoidarthritis,SLE,MSandasthmaTreg(CD4+,Foxp3+)Natural(developinthethymus)PreventeffectorTcelldevelopmentinLNInduced(developintheperiphery)DevelopundertheinfluenceofTGF-?InhibiteffectorTcellfunctioninperiphery.DevelopmentofTh17vsTregCellsWeaver,C.T.etal,Immunity24:677,2006BiologicactionsofCKs(2)StimulationofhemopoiesisSCF→stemcellsCSF→granulocytesandmonocytesIL-4andGM-CSF→dendriticcellsEPO→erythrocytesIL-11andTPO→plateletsIL-7,IL-15→formationofTmApoptosis,killingtargetcellTNF-α,FasLAngiogenesis

IL-8,VEGF,etc.

Cytokinereceptors1.

FivefamiliesImmunoglobulinsuperfamilyClassIcytokinereceptorfamilyClassIIcytokinereceptorfamilyTNFreceptorfamilyChemokinereceptorfamilyNote:Thereceptorcontainsadistinctsetof4spacedcysteinesintheirextracellulardomainsandaconservedsequencemotif(WSXWS)locatedneartheexternalmembranesurface.2.

Multi-subunitreceptorandcommon

receptorsubunitMulti-subunitreceptor

oneforcytokinebindinganotherforcytokinesignalingCommonreceptorsubunit

Thereissamereceptorsubunitforcytokinesignalingamongthedifferentcytokinereceptors.e.g.IL-2R

IL-5,GM-CSFIL-4,7,9,15IL-11,LIFRoleofIL-2andIL-2RinTcellproliferation.CKMajorSourceSizeActionsChromo.Location(h/m)GenomicOrgIL-2ActivatedTcells(Th1cells)h153aa/20aam169aa/20aa15.5kDaT-cellgrowthfactor,B-cellgrowth,Igproduction,J-chainexpression,InduceLAKactivity,Inducetumorinfiltratinglymphocyteactivity,AugmentNKactivity,Criticalroleinantigen-inducedcelldeath(AICD),Stimulatemacrophage/monocyteantitumoreffects4q26-27/34exonsIL-4ActivatedTcells(Th2Cells),CD4+NK1.1+NKTh153/24aam140aa/20Aa18kDaB-cellproliferation,Igclassswitch—IgG1,IgEproduction,AugmentMHCII,Fcεreceptors,IL-4RαandIL-2Rβexpression,Th2celldifferentiation,Antitumoreffects5q31.1/114exonsIL-7StromalcellsH177aa/25aam154aa/25aa17–25kDaThymocytegrowth,T-cellgrowth,Pre-Bcellgrowthinmicebutnothumans,SurvivalandgrowthofperipheralTcells8q12-13/36exonsIL-9ActivatedhelperTcellsh144aa/18aam144aa/18aa14kDaTh-helperclones,Erythroidprogenitors,BcellsMastcells,Fetalthymocytes5q31-35/135exonsIL-15MonocytesandmanyCellsoutsidetheimmunesystemh162aa/48aam162aa/48aa14–15kDaMast-cellgrowth,NK-celldevelopmentandactivity,T-cellproliferation4q67-279exonsIL-21ActivatedCD4+TcellsTFHcellsNKTcellsTh17cellsh162aa/31aam146aa/24aaComitogenforT-cellproliferation,InhibitsB-cellproliferationtoanti-IgM+IL-4,AugmentsB-cellproliferationtoanti-CD40,ConflictingreportsrelatedtoNKcells,CooperateswithIL-7andIL-15toexpandCD8cells,Antitumoreffects,DrivesterminalB-celldifferentiationtoplasmacells,ProapoptoticforBandNKcells4q67-27FeaturesofCytokinesWhoseReceptorsShareγcIn1993,itwasreportedthattheγchainwasdefectiveinpatientswithX-linkedseverecombinedimmunodeficiency(XSCID;thediseaseisformallydesignatedasSCIDX1)AbsentorprofoundlydiminishednumbersofTcellsandmitogenresponses.2.AbsenceofNKcells3.NormalnumbersofBcells,butdefectiveB-cellresponses.4.IgMcanbenormal,butgreatlydiminishedimmunoglobulinsofotherclasses.SCIDPatientwithsevereCandidainmouth.Contains3-6cysteine-richdomains.Eachdomainismadeupofapproximate40aminoacidresidues.GTP-bindingproteincoupledreceptorsuperfamily

orsevenpredicatedtransmembranedomainreceptorsuperfamily.SolublecytokinereceptorsIstheextracellularpartofthereceptorFunctions

1)antagonistofCKs:competitivelybindtoCK2)deliverytoolsofCKs3)indexofdiagnosisandprognosisofdiseases:sIL-2RMedicalapplicationofcytokinesorcytokinereceptoranalogsrIFN-:Intron-A,Referon-ArIFN-:ProkinerEPO:EpogenrG-CSFrGM-CSF:AcimmuneHumanTNFMcAb:HumiraTMTherapeuticApplicationsOnemightwanttodepresstheimmunesystem(forexample,toenhancegraftsurvival).Acloned,solubleformoftheIL-2receptorcantieupIL-2anddecreaseTHactivation.Alternately,anIL-2receptorantagonistcanalsodothis.Anti-TACbindstotheas