Intervention in endotoxin shock by sulfatide (I3SO3-GalCer) with a concomitant reduction in tumor necrosis factor...

Accumulating evidence indicates that tumor necrosis factor alpha (TNF-alpha) is a principal mediator of endotoxin shock. We previously reported that the action as well as the production of TNF requires the adhesion of leukocytes to the endothelium through integrin beta2 and intercellular adhesion molecule 1. In order to elucidate the roles of the initial interaction of the leukocytes with the endothelium through the selectins, we have examined the effects of a ligand for L- and P-selectins, sulfatide, on endotoxin shock in mice. Consistent with previous reports, a single injection of a high dose of endotoxin caused acute lethality, marked hypotension, leukopenia, and elevation in serum TNF-alpha levels. Pretreatment with sulfatide prevented acute lethality and hypotension, but not leukopenia, with a concomitant reduction in the increase in serum TNF-alpha levels. Moreover, pretreatment with sulfatide inhibited lipopolysaccharide (LPS)-induced TNF-alpha production by a human monocytic cell line, THP-1, in a dose-dependent manner. These results suggest either that selectin is critically involved in conferring the responsiveness of leukocytes to LPS or that sulfatide interferes with the intracellular signaling pathway which leads to TNF-alpha gene activation.