Most of the toxic reactions during Gram-negative infections are mediated by inflammatory cytokines induced by endotoxin, also termed lipopolysaccharide (LPS). To evaluate the possibility of synthetic derivatives of LPS to antagonize endotoxin-mediated activities, we have examined the effect of synthetic lipid A partial structures, precursor Ia (compound 406 or LA-14-PP) and lipid X (compound 401) on in vitro LPS or lipid A-induced release of tumor necrosis factor (TNF) by human peripheral blood mononuclear cells. In agreement with previous reports it was shown that LPS of Salmonella abortus equi and synthetic Escherichia coli-type lipid A (compound 506 or LA-15-PP) have potent TNF-inducing capacity. The maximum release of TNF was found after stimulation with 1 to 10 ng/ml of LPS or 10 to 1000 ng/ml of lipid A. Synthetic precursor Ia and lipid X failed to induce TNF release, but could inhibit LPS or lipid A-induced TNF release in a dose-dependent manner. Inhibition was not due to a shift of the kinetic of cytokine release, and was observed in the early stage of TNF production. Moreover, we found that the synergistic effect of interferon-gamma with LPS in induction of TNF release could also be counteracted by the addition of synthetic precursor Ia. The observation that precursor Ia failed to inhibit the induction of TNF by Bacillus Calmette-Guérin, Staphylococcus aureus cowan I or lipopeptide indicated that specific mechanisms are involved in suppression by lipid A partial structures on LPS-induced cytokine production.(ABSTRACT TRUNCATED AT 250 WORDS)