Diabetes, Vol 45, Issue 2 183-189, Copyright © 1996 by American Diabetes Association

ARTICLES

Tumor necrosis factor-alpha and interferon-gamma inhibit insulin secretion and cause DNA damage in unweaned-rat islets. Extent of nitric oxide involvement

A Dunger, JM Cunningham, CA Delaney, JE Lowe, MH Green, AJ Bone and IC Green
Institute of Diabetes, University of Greifswald, Karlsburg, Germany.

Nitric oxide has been implicated as one possible mediator of interleukin-1 beta (IL-1)-induced inhibition of insulin secretion and islet cell damage. The aim of this study was to define the effects of tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN) on nitric oxide production, insulin secretion, and DNA damage in islets from unweaned rats. Treatment of islets with 0.5-500 U/ml of either TNF or IFN on their own inhibited glucose-stimulated insulin secretion in a dose-dependent manner (minimum effective dose 5 U/ml). In combination, the cytokines exerted a pronounced synergistic inhibitory effect on secretion and were equipotent at causing a significant and concentration-dependent increase in culture medium nitrite levels, islet cyclic GMP formation, and DNA damage. Used alone or in combination, TNF and IFN significantly enhanced the activity of inducible nitric oxide synthase as determined by measuring the conversion of 14C-labeled arginine to 14C-labeled citrulline and nitric oxide. Use of arginine-free medium, without or with NG-monomethyl-L-arginine, resulted in inhibition of nitrite formation by 5-1,000 U/ml IFN+TNF and partial restoration of the insulin secretory response to glucose. Treatment of rat islets with increasing doses of TNF+IFN (5, 50, and 500 U/ml) resulted in a progressive increase in DNA damage, as shown by the comet assay, which detects DNA strand breaks in individual islet cells. The DNA damage caused by an intermediate concentration (50 U/ml) of TNF+IFN was comparable to that generated by IL-1 when used at 20 U/ml. We conclude that TNF and IFN induce nitric oxide formation, which partially inhibits glucose-induced insulin secretion and causes significant DNA strand breakage, but that as cytokine concentrations increase, non-nitric-oxide-mediated events predominate.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. S. Narang and R. I. Mahato Biological and biomaterial approaches for improved islet transplantation. Pharmacol. Rev., June 1, 2006; 58(2): 194 - 243. [Abstract] [Full Text] [PDF]

				T. Rydgren, D. Bengtsson, and S. Sandler Complete Protection Against Interleukin-1{beta}-Induced Functional Suppression and Cytokine-Mediated Cytotoxicity in Rat Pancreatic Islets In Vitro Using an Interleukin-1 Cytokine Trap. Diabetes, May 1, 2006; 55(5): 1407 - 1412. [Abstract] [Full Text] [PDF]

				J. He, I. Usui, K. Ishizuka, Y. Kanatani, K. Hiratani, M. Iwata, A. Bukhari, T. Haruta, T. Sasaoka, and M. Kobayashi Interleukin-1{alpha} Inhibits Insulin Signaling with Phosphorylating Insulin Receptor Substrate-1 on Serine Residues in 3T3-L1 Adipocytes Mol. Endocrinol., January 1, 2006; 20(1): 114 - 124. [Abstract] [Full Text] [PDF]

				N. Allaman-Pillet, J. Storling, A. Oberson, R. Roduit, S. Negri, C. Sauser, P. Nicod, J. S. Beckmann, D. F. Schorderet, T. Mandrup-Poulsen, et al. Calcium- and Proteasome-dependent Degradation of the JNK Scaffold Protein Islet-brain 1 J. Biol. Chem., December 5, 2003; 278(49): 48720 - 48726. [Abstract] [Full Text] [PDF]

				P. Sen, S. Bhattacharyya, M. Wallet, C. P. Wong, B. Poligone, M. Sen, A. S. Baldwin Jr., and R. Tisch NF-{kappa}B Hyperactivation Has Differential Effects on the APC Function of Nonobese Diabetic Mouse Macrophages J. Immunol., February 15, 2003; 170(4): 1770 - 1780. [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]

				S. Cottet, P. Dupraz, F. Hamburger, W. Dolci, M. Jaquet, and B. Thorens cFLIP Protein Prevents Tumor Necrosis Factor-{alpha}-Mediated Induction of Caspase-8-Dependent Apoptosis in Insulin-Secreting {beta}Tc-Tet Cells Diabetes, June 1, 2002; 51(6): 1805 - 1814. [Abstract] [Full Text] [PDF]

				S. E. Kahn The Importance of {beta}-Cell Failure in the Development and Progression of Type 2 Diabetes J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4047 - 4058. [Full Text] [PDF]

				N. Sekine, S. Fukumoto, T. Ishikawa, T. Okazaki, and T. Fujita GH Inhibits Interferon-{gamma}-Induced Signal Transducer and Activator of Transcription-1 Activation and Expression of the Inducible Isoform of Nitric Oxide Synthase in INS-1 Cells Endocrinology, September 1, 2001; 142(9): 3909 - 3916. [Abstract] [Full Text] [PDF]

				P. Newsholme Why Is L-Glutamine Metabolism Important to Cells of the Immune System in Health, Postinjury, Surgery or Infection? J. Nutr., September 1, 2001; 131(9): 2515S - 2522. [Abstract] [Full Text] [PDF]

				A. Rabinovitch, W. L. Suarez-Pinzon, K. Sooy, K. Strynadka, and S. Christakos Expression of Calbindin-D28k in a Pancreatic Islet {beta}-Cell Line Protects against Cytokine-Induced Apoptosis and Necrosis Endocrinology, August 1, 2001; 142(8): 3649 - 3655. [Abstract] [Full Text] [PDF]

				R. Henningsson, P. Alm, and I. Lundquist Evaluation of islet heme oxygenase-CO and nitric oxide synthase-NO pathways during acute endotoxemia Am J Physiol Cell Physiol, May 1, 2001; 280(5): C1242 - C1254. [Abstract] [Full Text] [PDF]

				B. W. Tobin, S. K. Leeper-Woodford, B. B. Hashemi, S. M. Smith, and C. F. Sams Altered TNF-{alpha}, glucose, insulin, and amino acids in islets of Langerhans cultured in a microgravity model system Am J Physiol Endocrinol Metab, January 1, 2001; 280(1): E92 - E102. [Abstract] [Full Text] [PDF]

				L. A. Stephens, H. E. Thomas, L. Ming, M. Grell RIMA DARWICHE, L. Volodin, and T. W. H. Kay Tumor Necrosis Factor-{alpha}-Activated Cell Death Pathways in NIT-1 Insulinoma Cells and Primary Pancreatic {beta} Cells Endocrinology, July 1, 1999; 140(7): 3219 - 3227. [Abstract] [Full Text]

				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]

				W. Schepp, K. Dehne, H. Herrmuth, K. Pfeffer, and C. Prinz Identification and functional importance of IL-1 receptors on rat parietal cells Am J Physiol Gastrointest Liver Physiol, November 1, 1998; 275(5): G1094 - G1105. [Abstract] [Full Text] [PDF]

				N. Mizuno, H. Yoshitomi, H. Ishida, H. Kuromi, J. Kawaki, Y. Seino, and S. Seino Altered bcl-2 and bax Expression and Intracellular Ca2+ Signaling in Apoptosis of Pancreatic Cells and the Impairment of Glucose-Induced Insulin Secretion Endocrinology, March 1, 1998; 139(3): 1429 - 1439. [Abstract] [Full Text] [PDF]

				S. Cottet, P. Dupraz, F. Hamburger, W. Dolci, M. Jaquet, and B. Thorens SOCS-1 Protein Prevents Janus Kinase/STAT-dependent Inhibition of beta Cell Insulin Gene Transcription and Secretion in Response to Interferon-gamma J. Biol. Chem., July 6, 2001; 276(28): 25862 - 25870. [Abstract] [Full Text] [PDF]