QUININE INHIBITS PRODUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA FROM HUMANALVEOLAR MACROPHAGES

Although tumor necrosis factor-alpha (TNF-alpha) produced by alveolar macrophages plays a key role in acute and chronic inflammatory states of the lung, the regulation of TNF-alpha synthesis remains to be eluci dated. Recently, a K channel blocker, quinine, has been reported to in hibit cell proliferation and protein synthesis in lymphocytes, implica ting physiologic roles for K channels in lymphocytes. The effect of qu inine on protein synthesis in human alveolar macrophages, however, has not been determined, although alveolar macrophages have been reported to have two types of K channels. Therefore, we investigated the effec t of quinine on TNF-alpha production from human alveolar macrophages. The production of TNF-alpha was induced by lipopolysaccharide (LPS) st imulation. We obtained the following results. First, LPS induced time- dependent activation of both types of K channels. Second, quinine inhi bited TNF-alpha release in a dose-dependent fashion at concentrations of 50 to 200 muM, concentrations capable of blocking both types of K c hannels, with no appreciable reduction of phagocytosis of latex beads. Third, the compound remarkably inhibited the expression of TNF-alpha mRNA without any appreciable effect on the expression of beta-actin mR NA. These results indicate that both types of K channels are activated by stimulation with LPS and that quinine, at concentrations required to inhibit K channels, specifically blocks TNF-alpha production of hum an alveolar macrophages at the level of gene transcription.