Staphylococcal enterotoxin A-induced hepatotoxicity is predominantly mediated by Fas ligand (CD95L).

OBJECTIVE

To determine the role of tumor necrosis factor alpha (TNF-alpha) and Fas ligand (FasL, CD95L) in superantigen-induced and endotoxin-induced liver injury.

SUMMARY BACKGROUND DATA: Gram-positive bacteria are increasingly common causes of sepsis and multiorgan failure, but the pathophysiologic mechanisms of superantigen-provoked hepatotoxicity remain elusive.

METHODS

Intravital fluorescence microscopy was used to study the liver microcirculation in mice challenged with superantigen (staphylococcal enterotoxin A, SEA) or endotoxin (lipopolysaccharide, LPS) combined with D-galactosamine.

RESULTS

Administration of 10 microg LPS and 50 microg SEA caused similar hepatocellular damage as determined by liver enzymes and apoptosis. Notably, TNF-alpha-deficient mice were completely protected against hepatic injury provoked by LPS, whereas no protection was observed in response to SEA. On the other hand, FasL-deficient mice were protected against liver injury induced by SEA, but no protection was found when challenged with LPS. LPS increased clear-cut leukocyte recruitment, whereas SEA had no significant effect on leukocyte responses in the liver microcirculation. Leukocyte responses to LPS were decreased by >56% in TNF-alpha gene-targeted animals. Moreover, antiadhesive therapy, ie, immunoneutralization of P-selectin, which is an effective inhibitor of leukocyte recruitment, protected against LPS-induced but not against SEA-induced hepatic damage.

CONCLUSIONS

These novel findings demonstrate that the mechanisms of hepatic injury in endotoxin-induced and superantigen-induced sepsis are principally different. On one hand, SEA-provoked hepatotoxicity is mediated by FasL and is not associated with leukocyte recruitment. On the other hand, liver damage provoked by LPS is mediated by TNF-alpha and characterized by prominent leukocyte responses. These data may facilitate development of more specific therapies against sepsis of different origins.