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This version published online on November 20, 2003
Endocrinology, doi:10.1210/en.2003-1200
A more recent version of this article appeared on March 1, 2004
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Submitted on September 10, 2003
Accepted on November 10, 2003

An octamer motif is required for activation of the inducible nitric oxide synthase promoter in pancreatic {beta}-cells

Martine I. Darville1*, Sara Terryn1, and Décio L. Eizirik1

1 Laboratory of Experimental Medicine, Université libre de Bruxelles, Brussels, Belgium

* To whom correspondence should be addressed. 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 {beta}-cell dysfunction in type 1 diabetes mellitus. We have previously shown that cytokine-induced iNOS expression is cycloheximide (CHX)-sensitive and requires NF-{kappa}B activation. In the present study, we show that an octamer motif located 20 bp downstream of the proximal NF-{kappa}B binding site in the rat iNOS promoter is critical for interleukin (IL)-1{beta} and interferon-{gamma}-induction of promoter activity in rat primary {beta}-cells and in insulin-producing RINm5F cells. In gel shift assays, the octamer motif bound constitutively the transcription factor Oct1. Neither Oct1 nor NF-{kappa}B binding activities were blocked by CHX, suggesting that other factor(s) synthesized in response to IL-1{beta} 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-1{beta}-induced iNOS promoter activity. These results suggest that Oct1, NF-{kappa}B and HMG-I(Y) co-operate for transactivation of the iNOS promoter in pancreatic {beta}-cells.
Key words: nitric oxide synthase • pancreatic {beta}-cell • interleukin-1 • Oct1 • HMG-I(Y) • diabetes mellitus




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