TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

TNF-relatedapoptosis-inducingligand�(TRAIL)�isamemberoftheTNFfamilywithpotentapoptosis-induc- ingpropertiesintumorcells.�Inparticular,�TRAILstronglysynergizeswithconventionalchemotherapeutic� drugstoinducetumorcelldeath.�Thus,�TRAILhasbeenproposedasapromisingfuturecancertherapy.�Little,� however,�isknownregardingwhattheroleofTRAILisinnormaluntransformedcellsandwhethertherapeutic� administrationofTRAIL,�aloneorincombinationwithotherapoptotictriggers,�maycausetissuedamage.� Inthisstudy,�weinvestigatedtheroleofTRAILinFas-induced�(CD95/Apo-1-induced)�hepatocyteapoptosis� andliverdamage.�WhileTRAILalonefailedtoinduceapoptosisinisolatedmurinehepatocytes,�itstrongly� amplifiedFas-inducedcelldeath.�Importantly,�endogenousTRAILwasfoundtocriticallyregulateanti-Fas� antibody-inducedhepatocyteapoptosis,�liverdamage,�andassociatedlethalityinvivo.�TRAILenhancedanti- Fas-inducedhepatocyteapoptosisthroughtheactivationofJNKanditsdownstreamsubstrate,�theproapop- toticBcl-2�homologBim.�Consistently,�TRAIL-�andBim-deficientmiceandwild-typemicetreatedwithaJNK� inhibitorwereprotectedagainstanti-Fas-inducedliverdamage.�WeconcludethatTRAILandBimareimpor- tantresponsemodifiersofhepatocyteapoptosisandidentifyliverdamageandlethalityasapossibleriskof� TRAIL-basedtumortherapy.