Inhibition of Interleukin-1β-Induced COX-2 and EP3 Gene Expression by Sodium Salicylate Enhances Pancreatic Islet β-Cell Function

Abstract

Previous work has suggested that functional interrelationships may exist between inhibition of insulin secretion by interleukin (IL)-1β and the endogenous synthesis of prostaglandin E₂ (PGE₂) in the pancreatic islet. These studies were performed to ascertain the relative abundance of E prostaglandin (EP) receptor mRNAs in tissues that are major targets, or major degradative sites, of insulin; to identify which EP receptor type mediates PGE₂ inhibition of insulin secretion in pancreatic islets; and to examine possible sites of action through which sodium salicylate might affect IL-1β/PGE₂ interactions. Real-time fluorescence-based RT-PCR indicated that EP3 is the most abundant EP receptor type in islets, liver, kidney, and epididymal fat. EP3 mRNA is the least, whereas EP2 mRNA is the most, abundant type in skeletal muscle. Misoprostol, an EP3 agonist, inhibited glucose-induced insulin secretion from islets, an event that was prevented by preincubation with pertussis toxin, by decreasing cAMP. Electromobility shift assays demonstrated that sodium salicylate inhibits IL-1β-induced nuclear factor-κB (NF-κB) activation. Sodium salicylate also prevented IL-1β from inducing EP3 and cyclooxygenase (COX)-2 gene expression in islets and thereby prevented IL-1β from inhibiting glucose-induced insulin secretion. These findings indicate that the sites of action through which sodium salicylate inhibits these negative effects of IL-1β on β-cell function include activation of NF-κB as well as generation of PGE₂ by COX-2.