ENDOTHELIN ENHANCES LIPOPOLYSACCHARIDE-INDUCED EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN RAT GLIAL-CELLS

Lipopolysaccharide is known to stimulate production of nitrite via exp ression of inducible nitric oxide (NO) synthase in not only macrophage s but also glial cells. We found that in glial cell cultures lipopolys accharide-stimulated inducible NO synthase expression and nitrite accu mulation were synergistically enhanced by pretreatment with endothelin , whereas endothelin itself did not induce these responses. Pretreatme nt with endothelin-1, endothelin-3, and the selective endothelin type B (ETB) receptor agonist IRL 1620 caused the same effect with similar potencies, suggesting that the synergism was mediated via the endothel in ETB receptor. A protein kinase C inhibitor, calphostin C, suppresse d endothelin-3-enhanced inducible NO synthase expression. Pretreatment with either endothelin-3 or phorbol ester enhanced lipopolysaccharide -induced production of tumor necrosis factor-alpha (TNF-alpha). Simult aneous addition of TNF-alpha increased lipopolysaccharide-stimulated i nducible NO synthase expression. These results suggest that the increa se in inducible NO synthase expression by endothelin was due to the el evated TNF-alpha production via protein kinase C. Our findings present the possibility that endothelin is implicated in neurotoxicity via en hancement of inducible NO synthase expression. (C) 1997 Elsevier Scien ce B.V.