LPS-induced liver injury ind-galactosamine-sensitized mice requires secreted TNF-α and the TNF-p55 receptor

Abstract

Lipopolysaccharide andd-galactosamine induced lethality and apoptotic liver injury is dependent on endogenously produced tumor necrosis factor (TNF)-α. The present study was undertaken to determine whether membrane-associated or secreted TNF-α signaling through the p55 or p75 receptor was responsible for survival and hepatic injury after lipopolysaccharide administration ind-galactosamine-sensitized mice. Transgenic mice expressing null forms of TNF-α, the p55 and p75 receptor, and mice expressing only a cell-associated form of TNF-α were challenged with 8 mgd-galactosamine and 100 ng lipopolysaccharide. Mortality and apoptotic liver injury were only seen in wild-type and p75 knockout mice. p75 Knockout mice had significantly higher concentrations of plasma TNF-α than any other experimental group ( P ≤ 0.05) and tended to have the highest mortality and liver injury. In contrast, p55 and TNF-α knockout mice and animals expressing only a cell-associated form of TNF-α exhibited no mortality or liver injury. We conclude that survival and apoptotic liver injury in response to lipopolysaccharide and d-galactosamine are dependent exclusively on secreted TNF-α signaling through the p55 receptor.