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Induction of Cyclooxygenase-2 Gene in Pancreatic ß-Cells by 12-Lipoxygenase Pathway Product 12-Hydroxyeicosatetraenoic Acid

Leslie and Susan Gonda (Goldschmied) Diabetes and Genetics Research Center, Department of Diabetes, Endocrinology, & Metabolism, City of Hope National Medical Center, Duarte, California 91010

Address all correspondence and requests for reprints to: David Bleich, M.D., Department of Diabetes, Endocrinology, & Metabolism, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, California 91010. E-mail: dbleich{at}coh.org.

Cyclooxygenase-2 (COX-2) gene and 12-lipoxygenase (12-LO) gene are preferentially expressed over other types of cyclooxygenase and lipoxygenase in pancreatic ß-cells. Inhibition of either COX-2 or 12-LO can prevent cytokine-induced pancreatic ß-cell dysfunction as defined by inhibition of glucose-stimulated insulin secretion. As cellular stress induces both genes and their respective end products in pancreatic ß-cells, we evaluated the role of 12-hydroxyeicosatetraenoic acid (HETE) on COX-2 gene expression, protein expression, and prostaglandin E2 (PGE2) production.

We demonstrate that 12-HETE significantly increases COX-2 gene expression and consequent product formation, whereas a closely related lipid, 15-HETE, does not. In addition, IL-1ß-stimulated prostaglandin E2 production is completely inhibited by a preferential lipoxygenase inhibitor cinnaminyl-3,4-dihydroxy--cyanocinnamate.

We then evaluated IL-1ß-induced PGE2 production in islets purified from control C57BL/6 mice and 12-LO knockout mice lacking cytokine-inducible 12-HETE. IL-1ß stimulated an 8-fold increase in PGE2 production in C57BL/6 islets but failed to stimulate PGE2 in 12-LO knockout islets. Addition of 12-HETE to 12-LO knockout islet cells produced a statistically significant rise in PGE2 production. Furthermore, 12-HETE, but not 15-HETE, stimulated COX-2 promoter and activator protein-1 binding activity. These data demonstrate that 12-HETE mediates cytokine-induced COX-2 gene transcription and resultant PGE2 production in pancreatic ß-cells.

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