Prostaglandin E2 Mediates Inhibition of Insulin Secretion by Interleukin-1β

Abstract

Interleukin-1␤ (IL-1␤) and prostaglandin E 2 (PGE 2 ), frequently co-participants in inflammatory states, are two well recognized inhibitors of glucose-induced insulin secretion. Previous reports have concluded that the inhibitory effects of these two autacoids on pancreatic ␤ cell function are not related because indomethacin, a potent prostaglandin synthesis inhibitor, does not prevent IL-1␤ effects. However, indomethacin is not a specific cyclooxygenase inhibitor, and its other pharmacologic effects are likely to inhibit insulin secretion independently. Since we recently observed that IL-1␤ induces cyclooxygenase-2 (COX-2) gene expression and PGE 2 synthesis in islet ␤ cells, we have reassessed the possibility that PGE 2 mediates IL-1␤ effects on ␤ function. By using two cell lines (HIT-T15 and ␤HC13) as well as Wistar rat isolated pancreatic islets, we examined the ability of two COX-2-specific antagonists, NS-398 and SC-236, to prevent IL-1␤ inhibition of insulin secretion. Both drugs prevented IL-1␤ from inducing PGE 2 synthesis and inhibiting insulin secretion; adding back exogenous PGE 2 re-established inhibition of insulin secretion in the presence of IL-1␤. We also found that EP3, the PGE 2 receptor subtype whose post-receptor effect is to decrease adenylyl cyclase activity and, thereby, insulin secretion, is the dominant mRNA subtype expressed. We conclude that endogenous PGE 2 mediates the inhibitory effects of exogenous IL-1␤ on ␤ cell function. Prostaglandin E 2 (PGE 2 )1 is known to be an inhibitor of glucose-induced insulin secretion from studies in a ␤ cell line (1, 2) and isolated and neonatal islets of Langerhans (3-6) as well as in vivo in both animal (7,8) and human (9 -11) studies. These findings have been reinforced by studies in which inhibitors of cyclooxygenase, hence PGE 2 synthesis, have augmented glucose-induced insulin secretion. The only discordant result in the latter category of studies has been observed when indomethacin was used as the cyclooxygenase inhibitor. This discrepant result can be attributed to other effects of indomethacin that would be expected to inhibit insulin secretion through adverse effects on exocytosis that are unrelated to its effects on prostaglandin synthesis (12).Interleukin-1␤ (IL-1␤) has been reported to have major inhibitory effects on ␤ cell function, especially under conditions of high glucose concentrations and prolonged exposure to this cytokine (13)(14)(15)(16). This is an especially relevant observation because many reports suggest that IL-1␤ is an important force in the pathogenesis of diabetes mellitus (17,18). Previously, studies have concluded that endogenous PGE 2 does not play a participatory role in the adverse effects of IL-1␤ on ␤ cell function (5, 6). Ironically, however, the drug that was chosen to test this hypothesis and found not to reverse IL-1␤ inhibitory effects on insulin secretion was indomethacin, which itself has independent inhibitory actions on ␤ cell exocytosis (12).Recently, it has been appreciated that the pancreatic is...

Adenoviral Overexpression of the Glutamylcysteine Ligase Catalytic Subunit Protects Pancreatic Islets against Oxidative Stress

“…Increases in islet IL-1␤ during the development of diabetes in an animal model have been reported (7). We reported that specific inhibitors of cyclooxygenase-2 and PGE 2 production prevent IL-1␤ from inhibiting glucose-induced insulin secretion in isolated islets (14). However, the effect of IL-1␤ that inhibits insulin secretion via ROS formation we identified in the current study appears to be independent from PGE 2 production because PGE 2 did not increase ROS levels.…”

“…However, the effect of IL-1␤ that inhibits insulin secretion via ROS formation we identified in the current study appears to be independent from PGE 2 production because PGE 2 did not increase ROS levels. The effect of IL-1␤ that is mediated by PGE 2 to inhibit glucoseinduced insulin secretion may be more potent than the corresponding ROS-mediated effect of IL-1␤ because GCLC overexpression only partially prevented the IL-1␤ inhibitory effect on insulin secretion, whereas treatment with specific cyclooxygenase-2 inhibitors completely prevented IL-1␤-induced inhibition of glucose-induced insulin secretion (14).…”

“…Sciences and an ABI Prism 7700 Sequence detector equipped with a thermocycler (Taqman TM technology) and a cooled charge-coupled device camera to detect fluorescence emission over a range of wavelengths (500 -650 nm) as described previously by our laboratory (14). Probe and primers designed to detect GCLC expression levels were based on the sequence for rat GCLC (GenBank TM accession number AF218362 (17)) and were designed to target the same region as probes used for Northern blot analyses as reported previously in the literature (18,19).…”

“…Isolation and Culture of Wistar Rat Islets-Islets from the pancreata of male Wistar rats were isolated and cultured as described previously (6,14).…”

Prostaglandin E2 regulates Foxo activity via the Akt pathway: implications for pancreatic islet beta cell dysfunction

“…In contrast to most mammalian cells, beta cells constitutively and dominantly produce the COX-2 isoform of PGE 2 -generating enzymes rather than COX-1 [5]. Prior studies have demonstrated that PGE 2 inhibits glucose-stimulated insulin secretion (GSIS) in clonal beta cells and isolated islets [6,7], and that selective inhibition of COX-2 attenuates the development of diabetes in the low-dose streptozotocin mouse model and protects rat islets from cytokine-induced inhibition of GSIS [8,9]. Despite the established role of PGE 2 in pancreatic beta cells, the exact molecular mechanisms of PGE 2 -mediated inhibition of insulin secretion remain poorly understood.…”