FUNCTION OF THE P55 TUMOR-NECROSIS-FACTOR RECEPTOR DEATH DOMAIN MEDIATED BY PHOSPHATIDYLCHOLINE-SPECIFIC PHOSPHOLIPASE-C

Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammation that has been implicated in the pathogenesis of devastating clinical s yndromes including septic shock. We have investigated the role of a TN F-responsive phosphatidylcholine-specific phospholipase C (PC-PLC) for the cytotoxic and proinflammatory activity of TNF. We show here that the cytotoxicity signaled for by the so-called ''death domain'' of til e p55 TNF receptor is associated with the activation of PC-PLC. The xa nthogenate tricyclodecan-9-yl (D609), a specific and selective inhibit or of PC-PLC, blocked the cytotoxic action of TNF on L929 and Wehi164 cells. In vivo, D609 prevented both adhesion molecule expression in th e pulmonary vasculature and the accompanying leukocyte infiltration in TNF-treated mice. More strikingly, D609 protects BALB/c mice from let hal shock induced either by TNF, lipopolysaccharide, or staphylococcal enterotoxin B. Together these findings imply PC-PLC as all important mediator of the pathogenic action of TNF, suggesting that PC-PLC may s erve as a novel target for anti-inflammatory tory TNF antagonists.