RIP1-Dependent and Independent Effects of Necrostatin-1 in Necrosis and T Cell Activation 英文参考文献.docVIP

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RIP1-Dependent and Independent Effects of Necrostatin-1 in Necrosis and T Cell Activation 英文参考文献.doc

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RIP1-Dependent and Independent Effects of Necrostatin-1 in Necrosis and T Cell Activation 英文参考文献

RIP1-DependentandIndependentEffectsof Necrostatin-1inNecrosisandTCellActivation YoungSikCho1.¤,ThomasMcQuade1.,HaibingZhang2,JiankeZhang2,FrancisKa-MingChan1,3* 1DepartmentofPathology,PrograminImmunologyandVirology,TheUniversityofMassachusettsMedicalSchool,Worcester,Massachusetts,UnitedStatesofAmerica, 2Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America, 3UMass DiabetesandEndocrinologyResearchCenter,TheUniversityofMassachusettsMedicalSchool,Worcester,Massachusetts,UnitedStatesofAmerica Abstract Background:Programmednecrosis/necroptosisisanemergingformofcelldeaththatplaysimportantrolesinmammalian developmentandtheimmunesystem.Thepro-necrotickinasesinthereceptorinteractingprotein(RIP)familyarecrucial mediatorsofprogrammednecrosis.Recentadvancesinnecrosisresearchhavebeengreatlyaidedbytheidentificationof chemical inhibitors that block programmed necrosis. Necrostatin-1 (Nec-1) and its derivatives were previously shown to targetthepro-necrotickinaseRIP1/RIPK1.TheprotectiveeffectconferredbyNec-1anditsderivativesinmanyexperimental modelsystemswasoftenattributedtotheinhibitionofRIP1function. Methodology/Principal Findings:WecomparedtheeffectofNec-1andsiRNA-mediatedsilencingofRIP1inthemurine fibrosarcoma celllineL929.TreatmentofL929cellswiththepan-caspaseinhibitorzVAD-fmkorexogenousTNFinduces necrosis. Strikingly, we found that siRNA-mediated silencing of RIP1 inhibited zVAD-fmk induced necrosis, but not TNF- induced necrosis. TNF-induced cell death in RIP1 knocked down L929 cells was inhibited by Nec-1, but not the caspase inhibitorzVAD-fmk.WefoundthatPKA-C1expression,butnotJnkorErkactivation,wasmoderatelyinhibitedbyNec-1. Moreover,wefoundthatNec-1inhibitsproximalTcellreceptorsignalingindependentofRIP1,leadingtoinhibitionofTcell proliferation. Conclusions/Significance:OurresultsrevealthatbesidesRIP1,Nec-1alsotargetsotherfactorscrucialfornecrosisinduction inL929cells.Inaddition,