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

Abstract

Cyclooxygenase-2 (COX-2) gene and 12-lipoxygenase (12-LO) gene are preferentially expressed over other types of cyclooxygenase and lipoxygenase in pancreatic beta-cells. Inhibition of either COX-2 or 12-LO can prevent cytokine-induced pancreatic beta-cell dysfunction as defined by inhibition of glucose-stimulated insulin secretion. As cellular stress induces both genes and their respective end products in pancreatic beta-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-1beta-stimulated prostaglandin E2 production is completely inhibited by a preferential lipoxygenase inhibitor cinnaminyl-3,4-dihydroxy-alpha-cyanocinnamate. We then evaluated IL-1beta-induced PGE2 production in islets purified from control C57BL/6 mice and 12-LO knockout mice lacking cytokine-inducible 12-HETE. IL-1beta 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 beta-cells.

n-3 polyunsaturated fatty acids and insulin secretion

“…COX2 gene expression and PGE 2 synthesis are induced by IL1b in isolated rat islets and various cell lines (Tran et al 1999). AA supplementation induces PGE 2 production in rat insulinoma cells RINm5F (Han et al 2002) but INS1 cells and islets that are genetically modified to express the Fat-1 transgene produce less PGE 2 under an AA challenge (Wei et al 2010). As mentioned previously, the Fat-1 gene enables the conversion of n-6 PUFA to n-3 PUFA in cells and results in a much lower n-6:n-3 fatty acid ratio (Kang 2007).…”

Maintaining Equilibrium by Selective Targeting of Cyclooxygenase Pathways

“…31 Alternatively, 12-LOX metabolites, such as 12-hydroxyeicosatetraenoic acid, that are inflammatory can exert a regulatory role on COX-2 gene transcription and PG production. 32 Interestingly, exogenous administration of anti-inflammatory epoxides or inhibition of soluble epoxide hydrolase, the enzyme that hydrolyzes anti-inflammatory epoxides to the corresponding diols, is anti-inflammatory in a variety of disease models. 31,33 Therefore, combination therapy with soluble epoxide hydrolase inhibitors and NSAIDs (at a reduced dose) promises the benefit of alleviating pain and inflammation while simultaneously reducing undesired adverse effects associated with NSAIDs.…”

Transcriptional Regulation of Cyclooxygenase-2 Gene in Pancreatic β-Cells

“…Moreover, hyperglycemia appears to induce COX-2 mRNA in cultured human pancreatic islets (23). Upon the addition of interleukin-1␤, COX-2 mRNA and protein typically increase 3-4-fold, whereas end product PGE 2 increases Ͼ100-fold (24).…”