LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-alpha and the TNF-p55 receptor

Lipopolysaccharide and D-galactosamine induced lethality and apoptotic live r injury is dependent on endogenously produced tumor necrosis factor (TNF)- alpha. The present study was undertaken to determine whether membrane-assoc iated or secreted TNF-alpha signaling through the p55 or p75 receptor was r esponsible for survival and hepatic injury after lipopolysaccharide adminis tration in D-galactosamine-sensitized mice. Transgenic mice expressing null forms Of TNF-alpha, the p55 and p75 receptor, and mice expressing only a c ell-associated form of TNF-alpha were challenged with 8 mg D-galactosamine and 100 ng lipopolysaccharide. Mortality and apoptotic liver injury were on ly seen in wild-type and p75 knockout mice, p75 Knockout mice had significa ntly higher concentrations of plasma TNF-alpha than any other experimental group (P less than or equal to 0.05) and tended to have the highest mortali ty and liver injury. In contrast, p55 and TNF-alpha knockout mice and anima ls expressing only a cell-associated form of TNF-alpha exhibited no mortali ty or liver injury. We conclude that survival and apoptotic liver injury in response to lipopolysaccharide and D-galactosamine are dependent exclusive ly on secreted TNF-alpha signaling through the p55 receptor.