Potential role of NO in modulation of COX-2 expression and PGE2 production in pancreatic beta-cells.
Cytokines have been implicated in pancreatic beta-cell destruction leading to type 1 diabetes. Exposure to interleukin-1beta (IL-1beta) of pancreatic beta-cells induces expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Subsequent formation of nitric oxide (NO) and prostaglandin E2 (PGE2) may impair beta-cell function. Using NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA), we have further investigated the relation between NO formation and COX-2 expression. IL-1beta stimulated the formation of NO and PGE2 by pancreatic beta-cells. L-NMMA completely inhibited IL-1beta-induced NO formation and attenuated PGE2 production. COX-2 gene transcription level and protein expression were determined by real-time PCR, Western blot and luciferase analysis. L-NMMA inhibited IL-1beta-induced promoter activity, gene transcription and protein expression of COX-2 in pancreatic beta-cells. Therefore, we concluded that NO-affected COX-2 activity is directly linked to COX-2 gene transcription and protein expression in pancreatic beta-cells. The identification of a novel interaction of NO on the COX signaling pathway in beta-cells provides a strategy of intervention for further evaluating the role of NO and PGE2 in autoimmune diabetes.
Ling
Jia-Jian
JJ
The Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 210029, China.
Sun
Yu-Jie
YJ
Zhu
Dong-Ya
DY
Chen
Qi
Q
Han
Xiao
X
D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors; D015971:Gene Expression Regulation, Enzymologic; D007375:Interleukin-1 / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D008156:Luciferases; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone