INTERVENTION IN ENDOTOXIN-SHOCK BY SULFATIDE ((ISO3)-S-3-GALCER) WITHA CONCOMITANT REDUCTION IN TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION

Accumulating evidence indicates that tumor necrosis factor alpha (TNF- alpha) is a principal mediator of endotoxin shock, We previously repor ted that the action as well as the production of TNF requires the adhe sion of leukocytes to the endothelium through integrin beta(2) and int ercellular adhesion molecule 1, In order to elucidate the roles of the initial interaction of the leukocytes with the endothelium through th e selectins, we have examined the effects of a ligand for L- and P-sel ectins, sulfatide, on endotoxin shock in mice, Consistent with previou s 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 a nd hypotension, but not leukopenia, with a concomitant reduction in th e increase in serum TNF-alpha levels, Moreover, pretreatment with sulf atide inhibited lipopolysaccharide (LPS)-induced TNF-a production by a human monocytic cell line, THP-1, in a dose-dependent manner, These r esults suggest either that selectin is critically involved in conferri ng the responsiveness of leukocytes to LPS or that sulfatide interfere s with the intracellular signaling pathway which leads to TNF-alpha ge ne activation.