Journal article
Fatal Hepatitis Mediated by Tumor Necrosis Factor TNFα Requires Caspase-8 and Involves the BH3-Only Proteins Bid and Bim
T Kaufmann, PJ Jost, M Pellegrini, H Puthalakath, R Gugasyan, S Gerondakis, E Cretney, MJ Smyth, J Silke, R Hakem, P Bouillet, TW Mak, VM Dixit, A Strasser
Immunity | Published : 2009
Abstract
Apoptotic death of hepatocytes, a contributor to many chronic and acute liver diseases, can be a consequence of overactivation of the immune system and is often mediated by TNFα. Injection with lipopolysaccharide (LPS) plus the transcriptional inhibitor D(+)-galactosamine (GalN) or mitogenic T cell activation causes fatal hepatocyte apoptosis in mice, which is mediated by TNFα, but the effector mechanisms remain unclear. Our analysis of gene-targeted mice showed that caspase-8 is essential for hepatocyte killing in both settings. Loss of Bid, the proapoptotic BH3-only protein activated by caspase-8 and essential for Fas ligand-induced hepatocyte killing, resulted only in a minor reduction of..
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Awarded by Juvenile Diabetes Research Foundation United States of America
Funding Acknowledgements
We are grateful to J. Adams, S. Cory, D. Huang, K. Rajewski, H. Koerner, and Y. Lazebnik for gifts of gene-targeted mice or antibodies. We thank K. Vella, N. lannarella, and G. Siciliano for animal care, C. Young and D. Chau for excellent technical assistance, M. Robati and B. Helbert for genotyping, the Biochemistry Department of the Royal Melbourne Hospital for ALT and AST measurements, and J. Adams, S. Cory, D. Huang, D. Vaux, and L. O'Reilly for advice and critical comments on the manuscript. This work was supported by grants (program #257502) and fellowships from the NHMRG (Canberra), the NCI (NIH, USA; #CA 80188 and #CA 43540), the Leukemia and Lymphoma Society of America (SCOR grant #7015), the JDRF/NHMRC, the Swiss National Science Foundation, the Roche Research Foundation, the Novarlis Foundation (formerly Ciba-Geigy-Jubilaeumsstiftung; postdoctoral fellowships to T.K.) and the Mildred-Scheel Stiftung/Deutsche Krebshilfe (postdoctoral fellowship to P.J.J.). V.M.D. is an employee at Genentech, Inc.