Primary and Malignant Cholangiocytes Undergo CD40 Mediated Fas Dependent Apoptosis, but Are Insensitive to Direct Activation with Exogenous Fas Ligand 英文参考文献.docVIP

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Primary and Malignant Cholangiocytes Undergo CD40 Mediated Fas Dependent Apoptosis, but Are Insensitive to Direct Activation with Exogenous Fas Ligand 英文参考文献.doc

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Primary and Malignant Cholangiocytes Undergo CD40 Mediated Fas Dependent Apoptosis, but Are Insensitive to Direct Activation with Exogenous Fas Ligand 英文参考文献

PrimaryandMalignantCholangiocytesUndergoCD40 MediatedFasDependentApoptosis,butAreInsensitive toDirectActivationwithExogenousFasLigand ElizabethH.Humphreys,KevinT.Williams,DavidH.Adams,SimonC.Afford* CentreforLiverResearch,MRCCentreforImmuneRegulation,TheInstituteofBiomedicalResearch,UniversityofBirmingham,Birmingham,UnitedKingdom Abstract Introduction: Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesisofwhichremainsuncertain.Nocommongeneticdefectshavebeendescribedbutitisacceptedthatchronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members;CD40andFas(CD95).FunctionaldeficiencyofCD154,theligandforCD40,leadstoafailureofclearanceofbiliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosisandthedevelopmentofcholangiocarcinoma. Aims:TodeterminewhethermalignantcholangiocytesdisplaydefectsinCD40mediatedapoptosis.BycomparingCD40 andFas-mediatedapoptosisandintracellularsignallinginprimaryhumancholangiocytesandthreecholangiocytecelllines. Results:PrimarycholangiocytesandcholangiocytecelllineswererelativelyinsensitivetodirectFas-mediatedkillingwith exogenousFasLwhencomparedwithJurkatcells,whichreadilyunderwentFas-mediatedapoptosis,butwereextremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignantcellsandwasSTAT-3andAP-1dependentinboth. Conclusions: 1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignantcholangiocytes2)TherelativeinsensitivityofcholangiocytestoFasactivationdemonstratestheimportanceof CD40 aug