Interleukin-1 Enhances Pancreatic Islet Arachidonic Acid 12-Lipoxygenase Product Generation by Increasing Substrate Availability through a Nitric Oxide-dependent Mechanism

Abstract

Interleukin-1 (IL-1) impairs insulin secretion from pancreatic islets and may contribute to the pathogenesis of insulin-dependent diabetes mellitus. IL-1 increases islet expression of nitric oxide (NO) synthase, and the resultant overproduction of NO participates in inhibition of insulin secretion because NO synthase inhibitors, e.g. N G -monomethyl-arginine (NMMA), prevent this inhibition. While exploring effects of IL-1 on islet arachidonic acid metabolism, we found that IL-1 increases islet production of the 12-lipoxygenase product 12-hydroxyeicosatetraenoic acid 12-(HETE). This effect requires NO production and is prevented by NMMA. Exploration of the mechanism of this effect indicates that it involves increased availabilty of the substrate arachidonic acid rather than enhanced expression of 12-lipoxygenase. Evidence supporting this conclusion includes the facts that IL-1 does not increase islet 12-lipoxygenase protein or mRNA levels and does not enhance islet conversion of exogenous arachidonate to 12-HETE. Mass spectrometric stereochemical analyses nonetheless indicate that 12-HETE produced by IL-1-treated islets consists only of the S-enantiomer and thus arises from enzyme action. IL-1 does enhance release of nonesterified arachidonate from islets, as measured by isotope dilution mass spectrometry, and this effect is suppressed by NMMA and mimicked by the NO-releasing compound 3-morpholinosydnonimine. Although IL-1 increases neither islet phospholipase A 2 (PLA 2 ) activities nor mRNA levels for cytosolic or secretory PLA 2 , a suicide substrate which inhibits an islet Ca 2؉ -independent PLA 2 prevents enhancement of islet arachidonate release by IL-1. IL-1 also impairs esterification of [ 3 H 8 ]arachidonate into islet phospholipids, and this effect is prevented by NMMA and mimicked by the mitochondrial ATP-synthase inhibitor oligomycin. Experiments with exogenous substrates indicate that NMMA does not inhibit and that the NO-releasing compound does not activate islet 12-lipoxygenase or PLA 2 activities. These results indicate that a novel action of NO is to increase levels of nonesterified arachidonic acid in islets.

Interleukin-1 Reduces the Glycolytic Utilization of Glucose by Pancreatic Islets and Reduces Glucokinase mRNA Content and Protein Synthesis by a Nitric Oxide-dependent Mechanism

“…We have recently reported that IL-1 also induces accumulation of nonesterified arachidonic acid in islets by an NO-dependent mechanism (6). Our findings suggested that this reflected suppression of re-esterification of arachidonic acid released during phospholipid turnover, but others have found that NO stimulates arachidonic acid release from macrophagelike cells by a mechanism involving accelerated glycolytic flux (13).…”

“…induces islet expression of the inducible isoform of nitric oxide synthase and overproduction of nitric oxide (NO) (1)(2)(3)(4)(5)(6). This is associated with inhibition of glucose-induced insulin secretion (7)(8)(9)(10) and impaired islet oxidation of glucose (8 -12), and both of these effects are prevented by the inducible nitric oxide synthase inhibitor N G -monomethylarginine (NMMA) (1, 2, 4), indicating that they occur through NO-dependent mechanisms.…”

Prolongation of islet allograft survival following ex vivo transduction with adenovirus encoding a soluble type 1 TNF receptor–Ig fusion decoy

“…This amount of each cytokine in combination has been shown to consistently impair glucose-induced insulin production in uninfected islets, as well as in those infected with the Ad-LacZ control virus. 7,8,17,18,[33][34][35][36][37][38][39] In dynamic glucose perifusion studies, we observed that TNFa addition for 18-24 h was sufficient to significantly reduce islet sensitivity to glucose (assessed by insulin production). The combination of TNFa and IL-1b almost completely suppressed insulin production ( Figure 1b and Table 1).…”

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

“…12-Lipoxygenase is expressed in rodent and human islets [11,[15][16][17][18] and is upregulated under conditions of metabolic and cytokine stress. Direct addition of 12-S-HETE can impair beta cell function or can lead to loss of human beta cell viability [13,15,16,[19][20][21][22]. Recent evidence indicates that increased expression of 12-lipoxygenase in islets is a common feature of both rodent and human models of type 1 and type 2 diabetes [11,13,15,17,22].…”