Protection against Fas-mediated and tumor necrosis factor receptor 1-mediated liver injury by blockade of FADD without loss of nuclear factor-kappa Bactivation

Objective To investigate the role of FADD (Fas-associated protein with deat h domain) in Fas and tumor necrosis factor receptor I (TNFR1)-mediated hepa tic injury and inflammatory response in vivo. Summary Background Data Fas and TNFR1 are cell surface molecules that trigg er apoptosis or inflammation on engagement by a specific ligand or antibody . FADD is recruited to the cytoplasmic domain of these receptors on their a ctivation and works as a common mediator to induce apoptosis. It is known t hat a blockade of FADD can inhibit apoptosis mediated by Fas or TNFR1 in vi tro. However, it is not known whether the blockade can prevent organ injury and whether the inflammatory cascade is affected in vivo. Methods A FADD deletion mutant lacking the death effector domain was introd uced into mice by transduction with an adenovirus vector, and the effect of this FADD dominant negative mutant was examined in several liver injury mo dels. Results Hepatic injury induced by anti-Fas monoclonal antibody or tumor nec rosis factor (TNF)-alpha plus D-galactosamine was markedly ameliorated by t he FADD dominant negative transduction, which abrogated the death rate. Fur ther, the FADD dominant negative transduction efficiently blocked T cell-me diated concanavalin A-induced hepatitis while not affecting TNF-alpha produ ction or TNF-alpha -induced nuclear factor-kappaB activation in the liver. Conclusions These results provide the basis for a novel therapeutic modalit y in which an unfavorable apoptotic process can be inhibited without affect ing a favorable response for liver regeneration; this would be relevant to the clinical treatment of acute and chronic liver diseases as well as to so me inflammatory disorders with hypercytokinemia, such as sepsis.