The enhancing effect of tumour necrosis factor-alpha (TNF-alpha) on oxidative stress with or without a sublethal dose of endotoxin was examined. The mortality of mice treated with recombinant human TNF-alpha (1 x 10(4) units/mouse, intravenously) and endotoxin (0.01-1 mg/kg, intraperitoneally) was dependent on the dose of endotoxin. The liver lipid peroxide level, superoxide anion generation and serum lactate dehydrogenase activity, especially serum lactate dehydrogenase-5 isozyme leakage, in mice 2-4 hr after administration of recombinant human TNF to endotoxin-pretreated mice (0.5 mg/kg, intraperitoneally) were markedly higher than in those without endotoxin, whereas the administration of recombinant human TNF significantly decreased the non-protein sulfhydryl level, superoxide dismutase and glutathione peroxide activities in the liver of endotoxin-injected mice compared with those in mice treated with recombinant human TNF or endotoxin alone. Furthermore, findings clearly demonstrated that J774A.1 cells stimulated with recombinant human TNF (1 x 10(4) units/ml) can effectively produce nitric oxide in the presence of endotoxin, and the production was dependent on the dose of endotoxin (0.01-10 micrograms/ml). The level of lipid peroxide in mice 4 hr after administration of recombinant human TNF and lead acetate (50 mg/kg, intravenously) was markedly higher than that in the mice treated with recombinant human TNF alone. By contrast, injection of polymyxin-B (20 mg/kg, intraperitoneally, an anti-endotoxin drug) markedly decreased the lipid peroxide level in the liver of the mice treated with recombinant human TNF and lead acetate. These findings suggest that the oxidative stress caused by TNF occurs as a enhancing effect of endotoxin or by bacterial translocation from the intestinal gut under reduction of reticuloendothelial system function in various disease states, and that the effect of TNF may cause a marked increase of toxicity of oxidative stress by endotoxin.

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We observed the effects of a chinese herb medicine Sho-saiko-to on the lethal and antitumor activities of recombinant human tumor necrosis factor (rhTNF) administered in mice. Sho-saiko-to was noted to protect the rhTNF-induced lethality in galactosamine-hypersensitized mice, and also Sho-saiko-to pretreated mice was protected against the decrease of rectal temperature after rhTNF administration. On the other hand, there was a remarkable enhancement of antitumor activity of rhTNF by Sho-saiko-to pretreatment.These results suggest that Sho-saiko-to drug may protect mice from severe shock syndrome induced by rhTNF.