Ursodeoxycholic acid inhibits the induction of nitric oxide synthase

Ursodeoxycholic acid was recently recognized as an effective agent in the treatment of primary biliary cirrhosis. Since the beneficial effect of ursodeoxycholic acid therapy appears to be mediated in part by an immune mechanism, we evaluated the effects of ursodeoxycholic acid on the synthesis of nitric oxide (NO), elevated production of which could be important in the pathogenesis of autoimmunity. Ursodeoxycholic acid (0.1-1000 microM) inhibited NO production by bacterial lipopolysaccharide-activated J774 macrophages in a concentration-dependent fashion, but the cytotoxicity was also evident at higher concentrations (250 and 1000 microM). Ursodeoxycholic acid did not have any effect on the activity of NO synthase that had already been induced. Treatment with lipopolysaccharide led to a significant expression of NO synthase mRNA that was significantly reduced by ursodeoxycholic acid. Findings indicated that ursodeoxycholic acid inhibited NO synthesis by inhibiting the induction of NO synthase, rather than its catalytic activity. Ursodeoxycholic acid therapy may exert a beneficial effect, in part, by attenuating the production of NO.