Send to

Choose Destination

See 1 citation found by title matching your search:

Ann Surg. 2001 Nov;234(5):681-8.

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

Author information

Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba Science City, Japan.



To investigate the role of FADD (Fas-associated protein with death domain) in Fas and tumor necrosis factor receptor 1 (TNFR1)-mediated hepatic injury and inflammatory response in vivo.


Fas and TNFR1 are cell surface molecules that trigger apoptosis or inflammation on engagement by a specific ligand or antibody. FADD is recruited to the cytoplasmic domain of these receptors on their activation and works as a common mediator to induce apoptosis. It is known that a blockade of FADD can inhibit apoptosis mediated by Fas or TNFR1 in vitro. However, it is not known whether the blockade can prevent organ injury and whether the inflammatory cascade is affected in vivo.


A FADD deletion mutant lacking the death effector domain was introduced into mice by transduction with an adenovirus vector, and the effect of this FADD dominant negative mutant was examined in several liver injury models.


Hepatic injury induced by anti-Fas monoclonal antibody or tumor necrosis factor (TNF)-alpha plus D-galactosamine was markedly ameliorated by the FADD dominant negative transduction, which abrogated the death rate. Further, the FADD dominant negative transduction efficiently blocked T cell- mediated concanavalin A-induced hepatitis while not affecting TNF-alpha production or TNF-alpha-induced nuclear factor-kappaB activation in the liver.


These results provide the basis for a novel therapeutic modality in which an unfavorable apoptotic process can be inhibited without affecting a favorable response for liver regeneration; this would be relevant to the clinical treatment of acute and chronic liver diseases as well as to some inflammatory disorders with hypercytokinemia, such as sepsis.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wolters Kluwer Icon for PubMed Central
Loading ...
Support Center