大学精品课件专业外语CytokinesWord文件下载.docx

大学精品课件专业外语CytokinesWord文件下载.docx

《大学精品课件专业外语CytokinesWord文件下载.docx》由会员分享，可在线阅读，更多相关《大学精品课件专业外语CytokinesWord文件下载.docx（8页珍藏版）》请在冰豆网上搜索。

Cytokinesareproteinssecretedbythecellsofinnateandadaptiveimmunitythatmediatemanyofthefunctionsofthesecells.Cytokinesareproducedinresponsetomicrobesandotherantigens,anddifferentcytokinesstimulatediverseresponsesofcellsinvolvedinimmunityandinflammation.Intheactivationphaseofadaptiveimmuneresponses,cytokinesstimulatethegrowthanddifferentiationoflymphocytes,andintheeffectorphasesofinnateandadaptiveimmunity,theyactivatedifferenteffectorcellstoeliminatemicrobesandotherantigens.Cytokinesalsostimulatethedevelopmentofhematopoieticcells.Inclinicalmedicine,cytokinesareimportantastherapeuticagentsandastargetsforspecificantagonistsinnumerousimmuneandinflammatorydiseases.

Thenomenclatureofcytokinesisoftenbasedontheircellularsources.Cytokinethatareproducedbymononuclearphageocyteswerecalledmonokines,andthoseproducedbylymphocyteswerecalledlymphokines.Withthedevelopmentofanticytokineantibodiesandmolecularprobes,itbecameclearthatthesameproteinmaybesynthesizedbylymphocytes,monocytes,andavarietyoftissuecells,includingendothelialcellsandsomeepithelialcells,.Therefore,thegenerictermcytokinesisthepreferrednameforthisclassofmediators.

GeneralPropertiesofCytokines

Cytokinesarepolypeptidesproducedinresponsetomicrobesandotherantigensthatmediateandregulateimmuneandinflammatoryreactions.Althoughcytokinesarestructurallydiverse,theyshareseveralproperties.

Cytokinesecretionisabrief,self-limitedevent.Cytokinesarenotusuallystoredaspreformedmolecules,andtheirsynthesisisinitiatedbynewgenetranscriptionasaresultofcellularactivation.Suchtranscriptionalactivationistransient,andthemessengerRNAsencodingmostcytokinesareunstable,socytokinesynthesisisalsotransient.TheproductionofsomecytokinesmayadditionallybecontrolledbyRNAprocessingandbypost-transcriptionalmechanisms,suchasproteolyticreleaseofanactiveproductfromaninactiveprecursor.Oncesynthesized,cytokinesarerapidlysecreted,resultinginaburstofreleaseasneeded.

Theactionsofcytokinesareoftenpleiotropicandredundant.Pleiotropismreferstotheabilityofonecytokinetoactondifferentcelltypes.Thispropertyallowsacytokinetomediatediversebiologiceffects,butitgreatlylimitsthetherapeuticuseofcytokinesbecauseadministrationofacytokineforadesiredclinicaleffectmayresultinnumerousunwantedsideeffects.Redundancyreferstothepropertyofmultiplecytokineshavingthesamefunctionaleffects.Becauseofthisredundancy,antagonistsagainstasinglecytokineormutationofonecytokinegenemaynothavefunctionalconsequences,asothercytokinesmaycompensate.

Cytokinesofteninfluencethesynthesisandactionsofothercytokines.Theabilityofonecytokinetosimulateproductionofothersleadstocascadesinwhichasecondorthirdcytokinemaymediatethebiologiceffectsofthefirst.Twocytokinesmayantagonizeeachother’saction,produceadditiveeffects,or,insomecases,producegreaterthananticipated,orsynergistic,effects.

Cytokineactionsmaybelocalandsystemic.Mostcytokinesactclosetowheretheyareproducedeitheronthesamecellthatsecretesthecytokine（autocrineaction）oronanearbycell（paracrineaction）.Tcellsoftensecretecytokinesatthesiteofcontactwithantigen-presentingcells,theso-calledimmunesynapse.Thismaybeonereasonthatcytokinesoftenactoncellsincontactwiththecytokineproducers.Whenproducedinlargeamounts,cytokinesmayenterthecirculationandactatadistancefromthesiteofproduction（endocrineaction）.

Cytokinesinitiatetheiractionsbybindingtospecificmembranereceptorsontargetcells.Receptorsforcytokinesoftenbindtheirligandswithhighaffinities,withdissociationconstants（Kdvalues）intherangeof10-10to10-12M.（Forcomparison,recallthatantibodiestypicallybindantigenswithaKdof10-7to10-11Mandthatmajorhistocompatibilitycomplex（MHC）moleculesbindpeptideswithaKdofonlyabout10-6M.）Asaconsequence,onlysmallquantitiesofacytokineareneededtooccupyreceptorsandelicitbiologiceffects.Mostcellsexpresslowlevelsofcytokinereceptors（ontheorderof100to1000receptorspercell）,butthisisadequateforinducingresponses.

Externalsignalsregulatetheexpressionofcytokinereceptorsandthustheresponsivenessofcellstocytokines.Forinstance,stimulationofTorBlymphocytesbyantigensleadstoincreasedexpressionofcytokinereceptors.Forthisreason,duringanimmuneresponse,theantigen-specificlymphocytesarethepreferentialresponderstosecretedcytokines.Thisisonemechanismformaintainingthespecificityofimmuneresponses,eventhoughcytokinesthemselvesarenotantigenspecific.Receptorexpressionisalsoregulatedbycytokinesthemselves,includingthesamecytokinethatbindstothereceptor,permittingpositiveamplificationornegativefeedback.

Thecellularresponsestomostcytokinesconsistofchangesingeneexpressionintargetcells,resultingintheexpressionofnewfunctionsandsometimesintheproliferationofthetargetcells.ManyofthechangesingeneexpressioninducedbycytokinesresultindifferentiationofTandBlymphocytesandactivationofeffectorcellssuchasmacrophages.Forinstance,cytokinesstimulateswitchingofantibodyisotypesinBcells,differentiationofhelperTcellsintoTH1andTH2subsets,andactivationofmicrobicidalmechanismsinphagocytes.Exceptionstotherulethatcytokinesworkbychanginggeneexpressionpatternsarechemokines,whichelicitrapidcellmigration,andacytokinecalledtumornecrosisfactor（TNF）,whichinducesapoptosisbyactivatingcellularenzymes,withoutnewgenetranscriptionorproteinsynthesis.

FunctionalCategoriesofCytokines

cytokineswereclassifiedintothreemainfunctionalcategoriesbasedontheirprincipalbiologicactions.

1.Mediatorsandregulatorsofinnateimmunityareproducedmainlybymononuclearphagocytesinresponsetoinfectiousagents.Bacterialproducts,suchaslipopolysaccharide（LPS）,andviralproducts,suchasdouble-strandedRNA,directlystimulatemacrophagestosecretethesecytokinesaspartofinnateimmunity.Thesamecytokinesmayalsobesecretedbymacrophagesthatareactivatedbyantigen-stimulatedTcells（i.e.,aspartofadaptivecell-mediatedimmunity）.Mostmembersofthisgroupofcytokinesactonendothelialcellsandleukocytestostimulatetheearlyinflammatoryreactionstomicrobes,andsomefunctiontocontroltheseresponses.NK（naturalkiller）cellsalsoproducecytokinesduringinnateimmunereactions.

2.MediatorsandregulatorsofadaptiveimmunityareproducedmainlybyTlymphocytesinresponsetospecificrecognitionofforeignantigens.SomeTcellcytokinesfunctionprimarilytoregulatethegrowthanddifferentiationofvariouslymphocytepopulationsandthusplayimportantrolesintheactivationphaseofTcell-dependentimmuneresponses.OtherTcell-derivedcytokinesrecruit,activate,andregulatespecializedeffectorcells,suchasmononuclearphagocytes,neutrophils,andeosinophils,toeliminateantigensintheeffectorphaseofadaptiveimmuneresponses.

3.Stimulatorsofhematopoiesisareproducedbybonemarrowstromalcells,leukocytes,andothercells,andstimulatethegrowthanddifferentiationofimmatureleukocytes.

Ingeneral,thecytokinesofinnateandadaptiveimmunityareproducedbydifferentcellpopulationsandactondifferenttargetcells.However,thesedistinctionsarenotabsolutebecausethesamecytokinemaybeproducedduringinnateandadaptiveimmunereactions,anddifferentcytokinesproducedduringsuchreactionsmayhaveoverlappingactions.

CytokineReceptorsandSignaling

Allcytokinereceptorsconsistofoneormoretransmembraneproteinswhoseextracellularportionsareresponsibleforcytokinebindingandwhosecytoplasmicportionsareresponsibleforinitiatingintracellularsignalingpathways.Thesesignalingpathwaysaretypicallyactivatedbyligand-inducedreceptorclustering,bringingtogetherthecytoplasmicportionsoftwoormorereceptormoleculesinaprocessanalogoustosignalingbyTandBcellreceptorsforantigens.

Themostwidelyusedclassificationofcytokinereceptorsisbasedonstructuralhomologiesamongtheextracellularcytokine-bindingdomains.Accordingtothisclassification,cytokinereceptorsaredividedintofivefamilies.

TypeIcytokinereceptors,alsocalledhemopoietimreceptors,containoneormorecopiesofadomainwithtwoconservedpairsofcysteineresiduesandmembraneproximalsequenceoftryptophanserineXtryptophanserine（WSXWS）,whereXisandaminoacid.Thesereceptorstypicallybindcytokinethatfoldintofourα-helicalstrands.Theconservedfeaturesofthereceptorspresumableformstructurethatbindfourα-helicalcytokines,butthespecificforindividualcytokinesisdeterminedbyaminoacidresiduesthatvaryfromonereceptortoanother.Thesereceptorsconsistofuniqueligand-bindingchainsandoneormoresignal-transducingchainwhichareoftensharedbyreceptorsfordifferentcytokines.

TypeⅡcytokinereceptorsaresimilartotypereceptorsbyvirtueoftwoextracellulardomainswhichconservedcysteines,buttypeⅡreceptorsdonotcontaintheWSXWSmotif.Thesereceptorsconsistofoneligand-bindingpolypeptidechainandsignal-transducingchain.

Somecytokinereceptorscontainextracellularimmunoglobulin（Ig）domainsandarethereforeclassifiedasmembersoftheIgsuperfamily.Thisgroupofreceptorsbindsdiversecytokinesthatsignalbydifferentmechanisms.

TNFreceptorsbel