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 syndromes including septic shock. We have investigated the role of a TNF-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 the p55 TNF receptor is associated with the activation of PC-PLC. The xanthogenate tricyclodecan-9-yl (D609), a specific and selective inhibitor of PC-PLC, blocked the cytotoxic action of TNF on L929 and Wehi164 cells. In vivo, D609 prevented both adhesion molecule expression in the pulmonary vasculature and the accompanying leukocyte infiltration in TNF-treated mice. More strikingly, D609 protects BALB/c mice from lethal shock induced either by TNF, lipopolysaccharide, or staphylococcal enterotoxin B. Together these findings imply PC-PLC as an important mediator of the pathogenic action of TNF, suggesting that PC-PLC may serve as a novel target for anti-inflammatory TNF antagonists.
Machleidt
T
T
Institut für Immunologie, Christian-Albrechts-Universität Kiel, Germany.
Krämer
B
B
Adam
D
D
Neumann
B
B
Schütze
S
S
Wiegmann
K
K
Krönke
M
M
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002460:Cell Line; D004768:Enterotoxins; D004789:Enzyme Activation; D051379:Mice; D009636:Norbornanes; D010713:Phosphatidylcholines / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012772:Shock, Septic / Q000517:prevention & control; D015398:Signal Transduction; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*
D015703:Antigens, CD; D001952:Bridged-Ring Compounds; D004768:Enterotoxins; D009636:Norbornanes; D010713:Phosphatidylcholines; D010726:Phosphodiesterase Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D013859:Thiocarbamates; D013871:Thiones; C031818:enterotoxin B, staphylococcal; C046498:tricyclodecane-9-yl-xanthogenate; D010741:Phospholipases A; D010738:Type C Phospholipases