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)-1␤ and the endogenous synthesis of prostaglandin E 2 (PGE 2 ) 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 PGE 2 inhibition of insulin secretion in pancreatic islets; and to examine possible sites of action through which sodium salicylate might affect IL-1␤/PGE 2 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-1␤-induced nuclear factor-B (NF-B) activation. Sodium salicylate also prevented IL-1␤ from inducing EP3 and cyclooxygenase (COX)-2 gene expression in islets and thereby prevented IL-1␤ from inhibiting glucose-induced insulin secretion. These findings indicate that the sites of action through which sodium salicylate inhibits these negative effects of IL-1␤ on ␤-cell function include activation of NF-B as well as generation of PGE 2 by COX-2.

Group X Secretory Phospholipase A2 Regulates Insulin Secretion through a Cyclooxygenase-2-dependent Mechanism

“…Treatment with L-798,106 caused a significant 2.9-fold increase in GSIS in MIN6-C cells (Fig. 4B) in accordance with previous reports (13,15). In the absence of L-798,106 MIN6-GX cells demonstrated a significant (ϳ30%) reduction in GSIS compared with MIN6-C cells, as shown above (Figs.…”

“…PGE2 exerts its effects by interacting with one or more of its four PGE2 (EP) receptors, EP1, EP2, EP3, and EP4 (14). EP3 is the most abundant PGE2 receptor expressed in islets (13,15). Upon binding to the EP3 receptor subtype, PGE2 decreases adenylyl cyclase activity with a subsequent reduction in cAMP (16), a known potentiator of GSIS (17).…”

Free Radicals and the Pathogenesis of Type 1 Diabetes

“…Among COX-2 products, PGE 2 is known to inhibit glucose-induced insulin release by ␤-cells (41,42). IL-1-induced inhibition of insulin secretion by islet 36 cells is mediated by PGE 2 (43). However, like other prostanoids, PGE 2 has both pro-and anti-inflammatory actions (44), and it is not yet clear whether PGE 2 formation by COX-2 in the islets has a protective or detrimental effect.…”

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

“…Therefore, inhibiting the nonspecific inflammatory response may protect transplanted islets and increase the success rate of IPIT. There have been several approaches already to improve the survival of transplanted islets by inhibiting the ensuing nonspecific inflammation (Arita et al, 1998;Ozmen et al, 2002;Tran et al, 2002;Moberg et al, 2003;Contreras et al, 2004;Goto et al, 2004;Yang et al, 2005;Jung et al, 2009).…”