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-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 (PLA) activities nor mRNA levels for cytosolic or secretory PLA, a suicide substrate which inhibits an islet Ca-independent PLA prevents enhancement of islet arachidonate release by IL-1. IL-1 also impairs esterification of [H]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 activities. These results indicate that a novel action of NO is to increase levels of nonesterified arachidonic acid in islets.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				M. McDuffie, N. A. Maybee, S. R. Keller, B. K. Stevens, J. C. Garmey, M. A. Morris, E. Kropf, C. Rival, K. Ma, J. D. Carter, et al. Nonobese Diabetic (NOD) Mice Congenic for a Targeted Deletion of 12/15-Lipoxygenase Are Protected From Autoimmune Diabetes Diabetes, January 1, 2008; 57(1): 199 - 208. [Abstract] [Full Text] [PDF]

				K. Uno, Y. Iuchi, J. Fujii, H. Sugata, K. Iijima, K. Kato, T. Shimosegawa, and T. Yoshimura In Vivo Study on Cross Talk between Inducible Nitric-Oxide Synthase and Cyclooxygenase in Rat Gastric Mucosa: Effect of Cyclooxygenase Activity on Nitric Oxide Production J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 995 - 1002. [Abstract] [Full Text] [PDF]

				S. Ramanadham, H. Song, S. Bao, F.-F. Hsu, S. Zhang, Z. Ma, C. Jin, and J. Turk Islet Complex Lipids: Involvement in the Actions of Group VIA Calcium-Independent Phospholipase A2 in {beta}-Cells Diabetes, February 1, 2004; 53(90001): S179 - 185. [Abstract] [Full Text]

				K. Eto, T. Yamashita, K. Hirose, Y. Tsubamoto, E. K. Ainscow, G. A. Rutter, S. Kimura, M. Noda, M. Iino, and T. Kadowaki Glucose metabolism and glutamate analog acutely alkalinize pH of insulin secretory vesicles of pancreatic {beta}-cells Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E262 - E271. [Abstract] [Full Text] [PDF]

				S. Canals, M. J. Casarejos, S. de Bernardo, E. Rodriguez-Martin, and M. A. Mena Nitric Oxide Triggers the Toxicity due to Glutathione Depletion in Midbrain Cultures through 12-Lipoxygenase J. Biol. Chem., June 6, 2003; 278(24): 21542 - 21549. [Abstract] [Full Text] [PDF]

				D. R. Laybutt, A. Sharma, D. C. Sgroi, J. Gaudet, S. Bonner-Weir, and G. C. Weir Genetic Regulation of Metabolic Pathways in beta -Cells Disrupted by Hyperglycemia J. Biol. Chem., March 22, 2002; 277(13): 10912 - 10921. [Abstract] [Full Text] [PDF]

				S. Ramanadham, F.-F. Hsu, A. Bohrer, Z. Ma, and J. Turk Studies of the Role of Group VI Phospholipase A2 in Fatty Acid Incorporation, Phospholipid Remodeling, Lysophosphatidylcholine Generation, and Secretagogue-induced Arachidonic Acid Release in Pancreatic Islets and Insulinoma Cells J. Biol. Chem., May 14, 1999; 274(20): 13915 - 13927. [Abstract] [Full Text] [PDF]

				Z. Ma, X. Wang, W. Nowatzke, S. Ramanadham, and J. Turk Human Pancreatic Islets Express mRNA Species Encoding Two Distinct Catalytically Active Isoforms of Group VI Phospholipase A2 (iPLA2) That Arise from an Exon-skipping Mechanism of Alternative Splicing of the Transcript from the iPLA2 Gene on Chromosome 22q13.1 J. Biol. Chem., April 2, 1999; 274(14): 9607 - 9616. [Abstract] [Full Text] [PDF]

				W. Nowatzke, S. Ramanadham, Z. Ma, F.-F. Hsu, A. Bohrer, and J. Turk Mass Spectrometric Evidence That Agents That Cause Loss of Ca2+ from Intracellular Compartments Induce Hydrolysis of Arachidonic Acid from Pancreatic Islet Membrane Phospholipids by a Mechanism That Does Not Require a Rise in Cytosolic Ca2+ Concentration Endocrinology, October 1, 1998; 139(10): 4073 - 4085. [Abstract] [Full Text] [PDF]

				A. Cane, M. Breton, K. Koumanov, G. Bereziat, and O. Colard Oxidant-induced arachidonic acid release and impairment of fatty acid acylation in vascular smooth muscle cells Am J Physiol Cell Physiol, April 1, 1998; 274(4): C1040 - C1046. [Abstract] [Full Text] [PDF]

				Z. Ma, M. Landt, A. Bohrer, S. Ramanadham, D. M. Kipnis, and J. Turk 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 J. Biol. Chem., July 11, 1997; 272(28): 17827 - 17835. [Abstract] [Full Text] [PDF]

				M. A. Balboa, J. Balsinde, S. S. Jones, and E. A. Dennis Identity between the Ca2+-independent Phospholipase A2 Enzymes from P388D1 Macrophages and Chinese Hamster Ovary Cells J. Biol. Chem., March 28, 1997; 272(13): 8576 - 8580. [Abstract] [Full Text] [PDF]

				J. Balsinde and E. A. Dennis Bromoenol Lactone Inhibits Magnesium-dependent Phosphatidate Phosphohydrolase and Blocks Triacylglycerol Biosynthesis in Mouse P388D1 Macrophages J. Biol. Chem., December 13, 1996; 271(50): 31937 - 31941. [Abstract] [Full Text] [PDF]

				Z. Ma, S. Ramanadham, M. Wohltmann, A. Bohrer, F.-F. Hsu, and J. Turk Studies of Insulin Secretory Responses and of Arachidonic Acid Incorporation into Phospholipids of Stably Transfected Insulinoma Cells That Overexpress Group VIA Phospholipase A2 (iPLA2beta ) Indicate a Signaling Rather Than a Housekeeping Role for iPLA2beta J. Biol. Chem., April 13, 2001; 276(16): 13198 - 13208. [Abstract] [Full Text] [PDF]

				M. K. Patricia, R. Natarajan, A. N. Dooley, F. Hernandez, J.-L. Gu, J. A. Berliner, J. J. Rossi, J. L. Nadler, R. S. Meidell, and C. C. Hedrick Adenoviral Delivery of a Leukocyte-Type 12 Lipoxygenase Ribozyme Inhibits Effects of Glucose and Platelet-Derived Growth Factor in Vascular Endothelial and Smooth Muscle Cells Circ. Res., April 13, 2001; 88(7): 659 - 665. [Abstract] [Full Text] [PDF]