Endocrinology, Vol 129, 3167-3173, Copyright © 1991 by Endocrine Society

ARTICLES

Interleukin-1 beta-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase

N Welsh, DL Eizirik, K Bendtzen and S Sandler
Department of Medical Cell Biology, Uppsala University, Sweden.

The aim of this study was to characterize the dynamics and functional relevance of interleukin-1 beta (IL-1 beta)-induced nitric oxide production in isolated pancreatic islets. Thus, islets were isolated from adult rats, precultured for 3-5 days in medium RPMI-1640 plus 10% fetal calf serum, and then exposed to IL-1 beta for different time periods, after which islet nitrite production and aconitase activity were determined. IL-1 beta (5 ng/ml) did not increase islet nitrite production during the first hour of incubation. Moreover, the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (Meth-arg; 5 mM) failed to prevent the initial (90 min) IL-1 beta-induced increase in islet insulin release. After 4, 7, and 24 h, however, nitrite production was increased by 50%, 93%, and 139%, respectively. Islet aconitase activity and glucose oxidation rates were decreased by 70% after incubation for 24 h with IL-1 beta. Both Meth-arg and N alpha-p- tosyl-L-lysine chloromethyl ketone (0.1 mM), a protease inhibitor, could completely counteract the IL-1 beta-induced increases in nitrite production and inhibition of aconitase activity and glucose oxidation rates. In a separate series of experiments, islets were incubated for 60 min with or without IL-1 beta and the RNA synthesis inhibitor actinomycin-D (5 micrograms/ml) and subsequently incubated for another 9 h without any additions. The presence of actinomycin-D during the 1-h IL-1 beta incubation period prevented the IL-1 beta-induced rise in nitrite production and the IL-1 beta-induced inhibition of aconitase activity and insulin release. It is concluded that IL-1 beta-induced nitric oxide production is a late event which requires gene transcription and does not mediate the initial stimulatory effects of IL-1 beta on beta-cell function. However, the gradually augmented rate of nitric oxide production may inhibit the enzyme aconitase, leading to a suppressed mitochondrial activity and a defective insulin release in response to nutrient secretagogues.

This article has been cited by other articles:

				D. Mokhtari, J. W. Myers, and N. Welsh The MAPK Kinase Kinase-1 Is Essential for Stress-Induced Pancreatic Islet Cell Death Endocrinology, June 1, 2008; 149(6): 3046 - 3053. [Abstract] [Full Text] [PDF]

				D. L. Eizirik, A. K. Cardozo, and M. Cnop The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus Endocr. Rev., February 1, 2008; 29(1): 42 - 61. [Abstract] [Full Text] [PDF]

				K. T. Chambers, S. M. Weber, and J. A. Corbett PGJ2-stimulated beta-cell apoptosis is associated with prolonged UPR activation Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1052 - E1061. [Abstract] [Full Text] [PDF]

				R. Hagerkvist, S. Sandler, D. Mokhtari, and N. Welsh Amelioration of diabetes by imatinib mesylate (Gleevec(R)): role of {beta}-cell NF-{kappa}B activation and anti-apoptotic preconditioning FASEB J, February 1, 2007; 21(2): 618 - 628. [Abstract] [Full Text] [PDF]

				J. J. Collier, P. T. Fueger, H. E. Hohmeier, and C. B. Newgard Pro- and Antiapoptotic Proteins Regulate Apoptosis but Do Not Protect Against Cytokine-Mediated Cytotoxicity in Rat Islets and {beta}-Cell Lines. Diabetes, May 1, 2006; 55(5): 1398 - 1406. [Abstract] [Full Text] [PDF]

				T. Yamazaki, H. Akiba, A. Koyanagi, M. Azuma, H. Yagita, and K. Okumura Blockade of B7-H1 on Macrophages Suppresses CD4+ T Cell Proliferation by Augmenting IFN-{gamma}-Induced Nitric Oxide Production J. Immunol., August 1, 2005; 175(3): 1586 - 1592. [Abstract] [Full Text] [PDF]

				N. R. Barshes, S. Wyllie, and J. A. Goss Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts J. Leukoc. Biol., May 1, 2005; 77(5): 587 - 597. [Abstract] [Full Text] [PDF]

				T. Sparre, M. R. Larsen, P. E. Heding, A. E. Karlsen, O. N. Jensen, and F. Pociot Unraveling the Pathogenesis of Type 1 Diabetes with Proteomics: Present And Future Directions Mol. Cell. Proteomics, April 1, 2005; 4(4): 441 - 457. [Abstract] [Full Text] [PDF]

				M. R. Heitmeier, C. B. Kelly, N. J. Ensor, K. A. Gibson, K. G. Mullis, J. A. Corbett, and T. J. Maziasz Role of Cyclooxygenase-2 in Cytokine-induced {beta}-Cell Dysfunction and Damage by Isolated Rat and Human Islets J. Biol. Chem., December 17, 2004; 279(51): 53145 - 53151. [Abstract] [Full Text] [PDF]

				S. M. Weber, A. L. Scarim, and J. A. Corbett PPAR{gamma} is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic {beta}-cells Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E329 - E336. [Abstract] [Full Text]

				M. Todaro, F. Di Gaudio, M. Lavitrano, G. Stassi, and G. Papaccio Islet {beta}-Cell Apoptosis Triggered in Vivo by Interleukin-1{beta} Is Not Related to the Inducible Nitric Oxide Synthase Pathway: Evidence for Mitochondrial Function Impairment and Lipoperoxidation Endocrinology, October 1, 2003; 144(10): 4264 - 4271. [Abstract] [Full Text] [PDF]

				U. Mehlhorn, A. Krahwinkel, H. J. Geissler, K. LaRosee, U. M. Fischer, O. Klass, M. Suedkamp, K. Hekmat, P. Tossios, and W. Bloch Nitrotyrosine and 8-isoprostane formation indicate free radical-mediated injury in hearts of patients subjected to cardioplegia J. Thorac. Cardiovasc. Surg., January 1, 2003; 125(1): 178 - 183. [Abstract] [Full Text] [PDF]

				R. Riachy, B. Vandewalle, J. Kerr Conte, E. Moerman, P. Sacchetti, B. Lukowiak, V. Gmyr, T. Bouckenooghe, M. Dubois, and F. Pattou 1,25-Dihydroxyvitamin D3 Protects RINm5F and Human Islet Cells against Cytokine-Induced Apoptosis: Implication of the Antiapoptotic Protein A20 Endocrinology, December 1, 2002; 143(12): 4809 - 4819. [Abstract] [Full Text] [PDF]

				H. Steinbrenner, T.-B.-T. Nguyen, U. Wohlrab, W. A. Scherbaum, and J. Seissler Effect of Proinflammatory Cytokines on Gene Expression of the Diabetes-Associated Autoantigen IA-2 in INS-1 Cells Endocrinology, October 1, 2002; 143(10): 3839 - 3845. [Abstract] [Full Text] [PDF]

				H. E. Thomas, R. Darwiche, J. A. Corbett, and T. W.H. Kay Interleukin-1 Plus {gamma}-Interferon-Induced Pancreatic {beta}-Cell Dysfunction Is Mediated by {beta}-Cell Nitric Oxide Production Diabetes, February 1, 2002; 51(2): 311 - 316. [Abstract] [Full Text] [PDF]

				A. L. Scarim, M. Arnush, L. A. Blair, J. Concepcion, M. R. Heitmeier, D. Scheuner, R. J. Kaufman, J. Ryerse, R. M. Buller, and J. A. Corbett Mechanisms of {beta}-Cell Death in Response to Double-Stranded (ds) RNA and Interferon-{{gamma}} : dsRNA-Dependent Protein Kinase Apoptosis and Nitric Oxide-Dependent Necrosis Am. J. Pathol., July 1, 2001; 159(1): 273 - 283. [Abstract] [Full Text] [PDF]

				A. K. Cardozo, M. Kruhøffer, R. Leeman, T. Ørntoft, and D. L. Eizirik Identification of Novel Cytokine-Induced Genes in Pancreatic {beta}-Cells by High-Density Oligonucleotide Arrays Diabetes, May 1, 2001; 50(5): 909 - 920. [Abstract] [Full Text]

				A. Hoorens, G. Stangé, D. Pavlovic, and D. Pipeleers Distinction Between Interleukin-1-Induced Necrosis and Apoptosis of Islet Cells Diabetes, March 1, 2001; 50(3): 551 - 557. [Abstract] [Full Text]

				M.-C. Chen, V. Paez-Espinosa, N. Welsh, and D. L. Eizirik Interleukin-1{beta} Regulates Phospholipase D-1 Expression in Rat Pancreatic {beta}-Cells Endocrinology, August 1, 2000; 141(8): 2822 - 2828. [Abstract] [Full Text] [PDF]

				J. Saldeen Cytokines Induce Both Necrosis and Apoptosis via a Common Bcl-2-Inhibitable Pathway in Rat Insulin-Producing Cells Endocrinology, June 1, 2000; 141(6): 2003 - 2010. [Abstract] [Full Text] [PDF]

				U. Mehlhorn, W. Bloch, A. Krahwinkel, K. LaRose, H.-J. Geissler, K. Hekmat, K. Addicks, and E. R. de Vivie Activation of myocardial constitutive nitric oxide synthase during coronary artery surgery Eur. J. Cardiothorac. Surg., March 1, 2000; 17(3): 305 - 311. [Abstract] [Full Text] [PDF]

				M. R. Heitmeier, A. L. Scarim, and J. A. Corbett Prolonged STAT1 Activation Is Associated with Interferon-gamma Priming for Interleukin-1-induced Inducible Nitric-oxide Synthase Expression by Islets of Langerhans J. Biol. Chem., October 8, 1999; 274(41): 29266 - 29273. [Abstract] [Full Text] [PDF]

				P. Maechler, L. Jornot, and C. B. Wollheim Hydrogen Peroxide Alters Mitochondrial Activation and Insulin Secretion in Pancreatic Beta Cells J. Biol. Chem., September 24, 1999; 274(39): 27905 - 27913. [Abstract] [Full Text] [PDF]

				J.-M. Lin, J. Sternesjö, S. Sandler, and P. Bergsten Preserved Pulsatile Insulin Release from Prediabetic Mouse Islets Endocrinology, September 1, 1999; 140(9): 3999 - 4004. [Abstract] [Full Text]

				C. Carlsson, L. A. Håkan Borg, and N. Welsh Sodium Palmitate Induces Partial Mitochondrial Uncoupling and Reactive Oxygen Species in Rat Pancreatic Islets in Vitro Endocrinology, August 1, 1999; 140(8): 3422 - 3428. [Abstract] [Full Text]

				M. R. Heitmeier, A. L. Scarim, and J. A. Corbett Double-stranded RNA Inhibits beta -Cell Function and Induces Islet Damage by Stimulating beta -Cell Production of Nitric Oxide J. Biol. Chem., April 30, 1999; 274(18): 12531 - 12536. [Abstract] [Full Text] [PDF]

				S. Mohr, H. Hallak, A. de Boitte, E. G. Lapetina, and B. Brune Nitric Oxide-induced S-Glutathionylation and Inactivation of Glyceraldehyde-3-phosphate Dehydrogenase J. Biol. Chem., April 2, 1999; 274(14): 9427 - 9430. [Abstract] [Full Text] [PDF]

				L. Wang, A. Bhattacharjee, Z. Zuo, F. Hu, R. E. Honkanen, P.-O. Berggren, and M. Li A Low Voltage-Activated Ca2+ Current Mediates Cytokine-Induced Pancreatic {beta}-Cell Death Endocrinology, March 1, 1999; 140(3): 1200 - 1204. [Abstract] [Full Text]

				A. L. Scarim, M. R. Heitmeier, and J. A. Corbett Heat Shock Inhibits Cytokine-Induced Nitric Oxide Synthase Expression by Rat and Human Islets Endocrinology, December 1, 1998; 139(12): 5050 - 5057. [Abstract] [Full Text] [PDF]

				J. Ye and S. G. Laychock A Protective Role for Heme Oxygenase Expression in Pancreatic Islets Exposed to Interleukin-1{beta} Endocrinology, October 1, 1998; 139(10): 4155 - 4163. [Abstract] [Full Text] [PDF]

				P.-O. Carlsson, S. Sandler, and L. Jansson Pancreatic Islet Blood Perfusion in the Nonobese Diabetic Mouse: Diabetes-Prone Female Mice Exhibit a Higher Blood Flow Compared with Male Mice in the Prediabetic Phase Endocrinology, August 1, 1998; 139(8): 3534 - 3541. [Abstract] [Full Text] [PDF]

				M. Arnush, A. L. Scarim, M. R. Heitmeier, C. B. Kelly, and J. A. Corbett Potential Role of Resident Islet Macrophage Activation in the Initiation of Autoimmune Diabetes J. Immunol., March 15, 1998; 160(6): 2684 - 2691. [Abstract] [Full Text] [PDF]

				A. L. Scarim, M. R. Heitmeier, and J. A. Corbett Irreversible Inhibition of Metabolic Function and Islet Destruction after a 36-Hour Exposure to Interleukin-1{beta} Endocrinology, December 1, 1997; 138(12): 5301 - 5307. [Abstract] [Full Text] [PDF]

				C. A. Delaney, D. Pavlovic, A. Hoorens, D. G. Pipeleers, and D. L. Eizirik Cytokines Induce Deoxyribonucleic Acid Strand Breaks and Apoptosis in Human Pancreatic Islet Cells Endocrinology, June 1, 1997; 138(6): 2610 - 2614. [Abstract] [Full Text] [PDF]

				M. R. Heitmeier, A. L. Scarim, and J. A. Corbett Interferon-gamma Increases the Sensitivity of Islets of Langerhans for Inducible Nitric-oxide Synthase Expression Induced by Interleukin 1 J. Biol. Chem., May 23, 1997; 272(21): 13697 - 13704. [Abstract] [Full Text] [PDF]

				V. B. Schini-Kerth, M. Boese, R. Busse, B. Fisslthaler, and A. Mulsch N-{alpha}-Tosyl-L-Lysine Chloromethylketone Prevents Expression of iNOS in Vascular Smooth Muscle by Blocking Activation of NF-{kappa}B Arterioscler. Thromb. Vasc. Biol., April 1, 1997; 17(4): 672 - 679. [Abstract] [Full Text]

				N. Welsh and N. Welsh Interleukin-1beta-induced Ceramide and Diacylglycerol Generation May Lead to Activation of the c-Jun NH(2)-terminal Kinase and the Transcription Factor ATF2 in the Insulin-producing Cell Line RINm5F J. Biol. Chem., April 5, 1996; 271(14): 8307 - 8312. [Abstract] [Full Text] [PDF]

				N. Giannoukakis, W. A. Rudert, M. Trucco, and P. D. Robbins Protection of Human Islets from the Effects of Interleukin-1beta by Adenoviral Gene Transfer of an Ikappa B Repressor J. Biol. Chem., November 17, 2000; 275(47): 36509 - 36513. [Abstract] [Full Text] [PDF]