TY - JOUR
T1 - Fatal Hepatitis Mediated by Tumor Necrosis Factor TNFα Requires Caspase-8 and Involves the BH3-Only Proteins Bid and Bim
AU - Kaufmann, Thomas
AU - Jost, Philipp J.
AU - Pellegrini, Marc
AU - Puthalakath, Hamsa
AU - Gugasyan, Raffi
AU - Gerondakis, Steve
AU - Cretney, Erika
AU - Smyth, Mark J.
AU - Silke, John
AU - Hakem, Razq
AU - Bouillet, Philippe
AU - Mak, Tak W.
AU - Dixit, Vishva M.
AU - Strasser, Andreas
PY - 2009/1/16
Y1 - 2009/1/16
N2 - 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 liver damage. However, combined loss of Bid and another BH3-only protein, Bim, activated by c-Jun N-terminal kinase (JNK), protected mice from LPS+GalN-induced hepatitis. These observations identify caspase-8 and the BH3-only proteins Bid and Bim as potential therapeutic targets for treatment of inflammatory liver diseases.
AB - 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 liver damage. However, combined loss of Bid and another BH3-only protein, Bim, activated by c-Jun N-terminal kinase (JNK), protected mice from LPS+GalN-induced hepatitis. These observations identify caspase-8 and the BH3-only proteins Bid and Bim as potential therapeutic targets for treatment of inflammatory liver diseases.
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=58149262908&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2008.10.017
DO - 10.1016/j.immuni.2008.10.017
M3 - Article
C2 - 19119023
AN - SCOPUS:58149262908
SN - 1074-7613
VL - 30
SP - 56
EP - 66
JO - Immunity
JF - Immunity
IS - 1
ER -