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LIVER AND BILIARY TRACT

Inducible nitric oxide synthase upregulates cyclooxygenase-2 in mouse cholangiocytes promoting cell growth

Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, Minnesota 55905

Submitted 30 December 2003 ; accepted in final form 14 February 2004

Both inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) have been implicated in the biliary tract carcinogenesis. However, it is not known whether these inflammatory mediators are induced by interdependent or parallel pathways. Because iNOS activity has been associated with diverse gene expression, the aim of this study was to determine whether iNOS induces COX-2. To address this objective, immortalized, but nonmalignant, murine cholangiocytes, 603B cells were employed for these studies. Both iNOS and COX-2 protein and mRNA were expressed in these cells. However, iNOS inhibition with either N-[3-(aminomethyl) benzyl]acetamidine or stable transfection with an iNOS antisense construct inhibited COX-2 mRNA and protein expression, an effect that was reversed by NO donors. COX-2 mRNA expression in 603B cells was reduced by pharmacological inhibitors of the p38 MAPK and JNK1/2 pathways. In contrast, neither inhibitors of the soluble guanylyl cyclase inhibitor/protein kinase G nor p42/44 MAPK pathways attenuated COX-2 mRNA expression. Finally, 603B cells grew at a rate threefold greater than 603B-iNOS antisense cells. The low growth rate of 603B-iNOS antisense cells could be restored to near that of the parent cell line with exogenous PGE_2. In conclusion, iNOS induces COX-2 expression in cholangiocytes, which promotes cell growth. COX-2 induction may contribute to iNOS-associated carcinogenesis.

antisense; cholangiocyte; p38 mitogen-activated protein kinase

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