Role of lipid A in the production of tumor necrosis factor and differences in antitumor activity between tumor necrosis factor and lipopolysaccharide.

The role of lipopolysaccharide (LPS) in the production of tumor necrosis factor (TNF) was examined. Alkaline treatment of LPS greatly reduced the TNF-producing activity of LPS, but TNF was produced when a large amount was injected. Free lipid A and lipid A-mouse serum albumin complex, which were prepared from the acid hydrolyzate, effectively induced TNF. However, the polysaccharide-rich fraction of the acid hydrolyzate was not capable of inducing TNF. Preincubation of LPS with polymixin B largely abrogated the TNF-producing activity of LPS. The differences in antitumor activity between TNF and LPS were also tested. TNF has a direct cytotoxicity against cancer cells in vitro but LPS does not. The activity of TNF was not inhibited by preincubation with polymixin B. Tumor necrosis in vivo was inhibited by preincubation of LPS with polymixin B but not by that of TNF. Galactosamine was found to induce susceptibility to the lethal effects of LPS, but did not influence the action of TNF. Lipid A is largely responsible for the TNF-inducing activity of LPS, but is not essential for the antitumor activity of TNF.