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An Octamer Motif Is Required for Activation of the Inducible Nitric Oxide Synthase Promoter in Pancreatic ß-Cells

Laboratory of Experimental Medicine, Université libre de Bruxelles, B-1070 Brussels, Belgium

Address all correspondence and requests for reprints to: M. I. Darville, Laboratory of Experimental Medicine, Université libre de Bruxelles, Route de Lennik, 808 CP618, B-1070 Brussels, Belgium. E-mail: mdarvill{at}ulb.ac.be.

Nitric oxide, generated by the inducible form of nitric oxide synthase (iNOS), is a potential mediator of cytokine-induced ß-cell dysfunction in type 1 diabetes mellitus. We have previously shown that cytokine-induced iNOS expression is cycloheximide (CHX) sensitive and requires nuclear factor-B (NF-B) activation. In the present study, we show that an octamer motif located 20 bp downstream of the proximal NF-B binding site in the rat iNOS promoter is critical for IL-1ß and interferon- induction of promoter activity in rat primary ß-cells and insulin-producing RINm5F cells. In gel shift assays, the octamer motif bound constitutively the transcription factor Oct1. Neither Oct1 nor NF-B binding activities were blocked by CHX, suggesting that other factor(s) synthesized in response to IL-1ß contribute to iNOS promoter induction. The high mobility group (HMG)-I(Y) protein also bound the proximal iNOS promoter region. HMG-I(Y) binding was decreased in cells treated with CHX and HMG-I(Y) silencing by RNA interference reduced IL-1ß-induced iNOS promoter activity. These results suggest that Oct1, NF-B, and HMG-I(Y) cooperate for transactivation of the iNOS promoter in pancreatic ß-cells.

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