Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice 英文参考文献.docVIP

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Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice 英文参考文献.doc

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Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice 英文参考文献

Donthamsettyetal.ComparativeHepatology2011,10:11 /content/10/1/11 RESEARCH OpenAccess ProtectionagainstFas-inducedfulminanthepatic failureinliverspecificintegrinlinkedkinase knockoutmice ShashikiranDonthamsetty,WendyMMars,AnneOrr,ChuanyueWuandGeorgeKMichalopoulos* Abstract Background:Programmedcelldeathorapoptosisisanessentialprocessfortissuehomeostasis.Hepatocyte apoptosisisacommonmechanismtomanyformsofliverdisease.Thisstudywasundertakentotesttheroleof ILKinhepatocytesurvivalandresponsetoinjuryusingaJo-2-inducedapoptosismodel. Methods:Forsurvivalexperiments,ILKKOandWTmicereceivedasingleintraperitonealinjectionoftheagonistic anti-FasmonoclonalantibodyJo-2atthelethaldose(0.4μg/gbodyweight)orsublethaldose(0.16μg/gbody weight).ForfurthermechanisticstudiessublethaldoseofFasmonoclonalantibodywaschosen. Results:Therewas100%mortalityintheWTmiceascomparedto50%intheKOmice.Wealsofoundthat hepatocytespecificILKKOmice(integrinlinkedkinase)diedmuchlaterthanWTmiceafterchallengewithalethal doseofFasagonistJo-2.AtsublethaldoseofJo-2,therewas20%mortalityinKOmicewithminimalapoptosis whereasWTmicedevelopedextensiveapoptosisandliverinjuryleadingto70%mortalityduetoliverfailureat 12h.Proteinsknowntobeassociatedwithcellsurvival/deathweredifferentiallyexpressedinthe2groups.InILK KOmicetherewasdownregulationofproapoptoticgenesandupregulationofantiapoptoticgenes. Conclusions:Mechanisticinsightsrevealedthatpro-survivalpathwayssuchasAkt,ERK1/2,andNFkBsignaling wereupregulatedintheILKKOmice.InhibitionofonlyNFkBandERK1/2signalingledtoanincreaseinthe susceptibilityofILKKOhepatocytestoJo-2-inducedapoptosis.ThesestudiessuggestthatILKeliminationfrom hepatocytesprotectsagainstJo-2inducedapoptosisbyupregulatingsurvivalpathways.FAKdecreasemayalso playaroleinthisprocess.TheresultspresentedshowthatthesignalingeffectsofILKrelatedtothesefunctions aremediatedinpartmediatedthroughNFkBandERK1/2signaling. Keywords:Integrinlinkedkinase,Jo-2,Apoptosis,ECMsignaling Background chromatincondensation,cellshrinkage