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...