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J. Biol. Chem., Vol. 279, Issue 51, 53145-53151, December 17, 2004

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Role of Cyclooxygenase-2 in Cytokine-induced -Cell Dysfunction and Damage by Isolated Rat and Human Islets^*

Monique R. Heitmeier, Colleen B. Kelly¶, Nancy J. Ensor, Kenneth A. Gibson, Karen G. Mullis, John A. Corbett¶, and Timothy J. Maziasz||

From the Departments of Cardiovascular and Metabolic Diseases and ^||Arthritis and Inflammation, Pfizer Global Research and Development, St. Louis, Missouri 63017 and the ^¶Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri 63104

Type I diabetes mellitus is an autoimmune disease characterized by the selective destruction of the insulin-secreting -cell found in pancreatic islets of Langerhans. Cytokines such as interleukin-1 (IL-1), interferon- (IFN-), and tumor necrosis factor- (TNF-) mediate -cell dysfunction and islet degeneration, in part, through the induction of the inducible isoform of nitric-oxide synthase and the production of nitric oxide by -cells. Cytokines also stimulate the expression of the inducible isoform of cyclooxygenase, COX-2, and the production of prostaglandin E₂ (PGE₂) by rat and human islets; however, the role of increased COX-2 expression and PGE₂ production in mediating cytokine-induced inhibition of islet metabolic function and viability has been incompletely characterized. In this study, we have shown that treatment of rat islets with IL-1 or human islets with a cytokine mixture containing IL-1 + IFN- ± TNF- stimulates COX-2 expression and PGE₂ formation in a time-dependent manner. Co-incubation of rat and human islets with selective COX-2 inhibitors SC-58236 and Celecoxib, respectively, attenuated cytokine-induced PGE₂ formation. However, these inhibitors failed to prevent cytokine-mediated inhibition of insulin secretion or islet degeneration. These findings indicate that selective inhibition of COX-2 activity does not protect rat and human islets from cytokine-induced -cell dysfunction and islet degeneration and, furthermore, that islet production of PGE₂ does not mediate these inhibitory and destructive effects.

Received for publication, September 23, 2004

^* This work was supported in part by National Institutes of Health Grants DK 52194 and DK 68839 (to J. A. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, 700 Chesterfield Pkwy. West, Mail Code T2C, St. Louis, MO 63017. Tel.: 314-274-3890; Fax: 314-274-8948, E-mail: Monique.R.Heitmeier{at}Pfizer.com.

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