Tenidap is a novel antirheumatic drug that combines cyclooxygenase inhibition with cytokine modulating qualities. We demonstrate here that tenidap inhibits the zymosan-induced expression of both interleukin 1 and tumor necrosis factor a in macrophages, at the mRNA and protein levels. The concentration-dependence of the tenidap-induced inhibition of the expression of mRNA for these proinflammatory cytokines agrees with that of its inhibitory effects on zymosan-induced arachidonate mobilization and changes in phosphoprotein pattern. The effects of tenidap on the lipopolysaccharide-induced expression of these cytokines are more complex. Tenidap inhibits the induction of interleukin 1 by lipopolysaccharide or bacteria, but less potently than the interleukin 1-response induced by zymosan. In contrast, the drug markedly potentiates the lipopolysaccharide-induced expression of tumor necrosis factor α at both the mRNA and protein levels. The latter effect is demonstrated to be due to cyclooxygenase inhibition and is reversed by prostaglandin E 2.