Induction of inducible nitric oxide synthase and heme oxygenase-1 in rat glial cells

Recent observations suggest a possible interaction between the nitric oxide (NO)/NO synthases and carbon monoxide (CO)/heme oxygenases systems. We examined the effects of lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and NO donor such as S-nitroso-N-acetylpenicillamine (SNAP) on induction of inducible NO synthase (iNOS) and heme oxygenase-1 (HO-1) in mixed glial cells and in rat hippocampus. In in vitro glial cells, treatment with LPS induced the expression of 130-kDa INOS after 6 h, and NO2- accumulation and enhancement of the protein level of 33-kDa HO-1 after 12h. In addition, treatment with SNAP induced HO-1 expression after 6 h. Although a NOS inhibitor, such as N-G-nitro-L-arginine (NNA), did not change LPS-induced iNOS expression, the inhibitor suppressed both NO2- accumulation and the enhancement of HO-1. Immunocytochemistry showed that LPS-treatment induced iNOS-immunoreactivity predominantly in microglia, while this treatment induced HO-1-immunoreactivity in both microglia and astrocytes. These results suggest that endogenous NO production by INOS in microglia causes autocrine-and paracrine-induction of HO-1 protein in microglia and astrocytes in rat brain.