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. 1992 Oct 1;287(Pt 1):229–235. doi: 10.1042/bj2870229

Nitric oxide and cyclic GMP formation induced by interleukin 1 beta in islets of Langerhans. Evidence for an effector role of nitric oxide in islet dysfunction.

J A Corbett 1, J L Wang 1, J H Hughes 1, B A Wolf 1, M A Sweetland 1, J R Lancaster Jr 1, M L McDaniel 1
PMCID: PMC1133148  PMID: 1384465

Abstract

Treatment of pancreatic islets with interleukin 1 (IL-1) results in a time-dependent inhibition of glucose-stimulated insulin secretion which has recently been demonstrated to be dependent on the metabolism of L-arginine to nitric oxide. In this report IL-1 beta is shown to induce the accumulation of cyclic GMP (cGMP) in a time-dependent fashion that mimics the time-dependent inhibition of insulin secretion by IL-1 beta. The accumulation of cGMP is dependent on nitric oxide synthase activity, since NG-monomethyl-L-arginine (a competitive inhibitor of nitric oxide synthase) prevents IL-1 beta-induced cGMP accumulation. cGMP formation and nitrite production induced by IL-1 beta pretreatment of islets are also blocked by the protein synthesis inhibitor, cycloheximide. The formation of cGMP does not appear to mediate the inhibitory effects of IL-1 beta on insulin secretion since a concentration of cycloheximide (1 microM) that blocks IL-1 beta-induced inhibition of glucose-stimulated insulin secretion and nitric oxide formation does not prevent cGMP accumulation, thus dissociating the two events. By using e.p.r. spectroscopy, IL-1 beta is shown to induce the formation of a g = 2.04 iron-nitrosyl feature in islets which is prevented by cycloheximide, demonstrating the requirement of protein synthesis for IL-1 beta-induced nitric oxide formation. Iron-nitrosyl complex-formation by islets confirms that IL-1 beta induces the generation of nitric oxide by islets, and provides evidence indicating that nitric oxide mediates destruction of iron-sulphur clusters of iron-containing enzymes. Consistent with the destruction of iron-sulphur centres is the finding that pretreatment of islets with IL-1 beta results in an approx. 60% inhibition of mitochondrial oxidation of D-glucose to CO2. Inhibition of islet glucose oxidation appears to be mediated by nitric oxide since both NMMA and cycloheximide prevent IL-1 beta-induced inhibition of glucose oxidation. These results show that IL-1 beta-induced nitric oxide formation parallels the ability of IL-1 beta to inhibit glucose-stimulated insulin secretion by islets, and that protein synthesis is required for IL-1 beta-induced nitric oxide formation. These results also suggest that nitric oxide mediates IL-1 beta-induced inhibitory effects on the pancreatic beta-cell by functioning as an effector molecule responsible for the destruction of iron-sulphur centres of iron-containing proteins, resulting in an impairment of mitochondrial function.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bredt D. S., Snyder S. H. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A. 1990 Jan;87(2):682–685. doi: 10.1073/pnas.87.2.682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Comens P. G., Wolf B. A., Unanue E. R., Lacy P. E., McDaniel M. L. Interleukin 1 is potent modulator of insulin secretion from isolated rat islets of Langerhans. Diabetes. 1987 Aug;36(8):963–970. doi: 10.2337/diab.36.8.963. [DOI] [PubMed] [Google Scholar]
  3. Corbett J. A., Lancaster J. R., Jr, Sweetland M. A., McDaniel M. L. Interleukin-1 beta-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. Role of nitric oxide in interleukin-1 beta-induced inhibition of insulin secretion. J Biol Chem. 1991 Nov 15;266(32):21351–21354. [PubMed] [Google Scholar]
  4. Dower S. K., Kronheim S. R., Hopp T. P., Cantrell M., Deeley M., Gillis S., Henney C. S., Urdal D. L. The cell surface receptors for interleukin-1 alpha and interleukin-1 beta are identical. Nature. 1986 Nov 20;324(6094):266–268. doi: 10.1038/324266a0. [DOI] [PubMed] [Google Scholar]
  5. Drapier J. C., Hibbs J. B., Jr Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible. J Clin Invest. 1986 Sep;78(3):790–797. doi: 10.1172/JCI112642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Drapier J. C., Pellat C., Henry Y. Generation of EPR-detectable nitrosyl-iron complexes in tumor target cells cocultured with activated macrophages. J Biol Chem. 1991 Jun 5;266(16):10162–10167. [PubMed] [Google Scholar]
  7. Eizirik D. L. Interleukin-1 induced impairment in pancreatic islet oxidative metabolism of glucose is potentiated by tumor necrosis factor. Acta Endocrinol (Copenh) 1988 Nov;119(3):321–325. doi: 10.1530/acta.0.1190321. [DOI] [PubMed] [Google Scholar]
  8. Granger D. L., Lehninger A. L. Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells. J Cell Biol. 1982 Nov;95(2 Pt 1):527–535. doi: 10.1083/jcb.95.2.527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Green L. C., Wagner D. A., Glogowski J., Skipper P. L., Wishnok J. S., Tannenbaum S. R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982 Oct;126(1):131–138. doi: 10.1016/0003-2697(82)90118-x. [DOI] [PubMed] [Google Scholar]
  10. Hibbs J. B., Jr, Taintor R. R., Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987 Jan 23;235(4787):473–476. doi: 10.1126/science.2432665. [DOI] [PubMed] [Google Scholar]
  11. Hughes J. H., Colca J. R., Easom R. A., Turk J., McDaniel M. L. Interleukin 1 inhibits insulin secretion from isolated rat pancreatic islets by a process that requires gene transcription and mRNA translation. J Clin Invest. 1990 Sep;86(3):856–863. doi: 10.1172/JCI114785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lancaster J. R., Jr, Hibbs J. B., Jr EPR demonstration of iron-nitrosyl complex formation by cytotoxic activated macrophages. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1223–1227. doi: 10.1073/pnas.87.3.1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Laychock S. G. Mediation of insulin release by cGMP and cAMP in a starved animal model. Mol Cell Endocrinol. 1983 Oct;32(2-3):157–170. doi: 10.1016/0303-7207(83)90079-5. [DOI] [PubMed] [Google Scholar]
  14. Mandrup-Poulsen T., Spinas G. A., Prowse S. J., Hansen B. S., Jørgensen D. W., Bendtzen K., Nielsen J. H., Nerup J. Islet cytotoxicity of interleukin 1. Influence of culture conditions and islet donor characteristics. Diabetes. 1987 May;36(5):641–647. doi: 10.2337/diab.36.5.641. [DOI] [PubMed] [Google Scholar]
  15. Marletta M. A., Yoon P. S., Iyengar R., Leaf C. D., Wishnok J. S. Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate. Biochemistry. 1988 Nov 29;27(24):8706–8711. doi: 10.1021/bi00424a003. [DOI] [PubMed] [Google Scholar]
  16. McDaniel M. L., Colca J. R., Kotagal N., Lacy P. E. A subcellular fractionation approach for studying insulin release mechanisms and calcium metabolism in islets of Langerhans. Methods Enzymol. 1983;98:182–200. doi: 10.1016/0076-6879(83)98149-1. [DOI] [PubMed] [Google Scholar]
  17. McDaniel M. L., King S., Anderson S., Fink J., Lacy P. E. Effect of cytochalasin B on hexose transport and glucose metabolism in pancreatic islets. Diabetologia. 1974 Aug;10(4):303–308. doi: 10.1007/BF02627731. [DOI] [PubMed] [Google Scholar]
  18. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  19. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  20. Pellat C., Henry Y., Drapier J. C. IFN-gamma-activated macrophages: detection by electron paramagnetic resonance of complexes between L-arginine-derived nitric oxide and non-heme iron proteins. Biochem Biophys Res Commun. 1990 Jan 15;166(1):119–125. doi: 10.1016/0006-291x(90)91919-j. [DOI] [PubMed] [Google Scholar]
  21. Reddy D., Lancaster J. R., Jr, Cornforth D. P. Nitrite inhibition of Clostridium botulinum: electron spin resonance detection of iron-nitric oxide complexes. Science. 1983 Aug 19;221(4612):769–770. doi: 10.1126/science.6308761. [DOI] [PubMed] [Google Scholar]
  22. Sandler S., Andersson A., Hellerström C. Inhibitory effects of interleukin 1 on insulin secretion, insulin biosynthesis, and oxidative metabolism of isolated rat pancreatic islets. Endocrinology. 1987 Oct;121(4):1424–1431. doi: 10.1210/endo-121-4-1424. [DOI] [PubMed] [Google Scholar]
  23. Sandler S., Bendtzen K., Borg L. A., Eizirik D. L., Strandell E., Welsh N. Studies on the mechanisms causing inhibition of insulin secretion in rat pancreatic islets exposed to human interleukin-1 beta indicate a perturbation in the mitochondrial function. Endocrinology. 1989 Mar;124(3):1492–1501. doi: 10.1210/endo-124-3-1492. [DOI] [PubMed] [Google Scholar]
  24. Southern C., Schulster D., Green I. C. Inhibition of insulin secretion by interleukin-1 beta and tumour necrosis factor-alpha via an L-arginine-dependent nitric oxide generating mechanism. FEBS Lett. 1990 Dec 10;276(1-2):42–44. doi: 10.1016/0014-5793(90)80502-a. [DOI] [PubMed] [Google Scholar]
  25. Stadler J., Billiar T. R., Curran R. D., Stuehr D. J., Ochoa J. B., Simmons R. L. Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes. Am J Physiol. 1991 May;260(5 Pt 1):C910–C916. doi: 10.1152/ajpcell.1991.260.5.C910. [DOI] [PubMed] [Google Scholar]
  26. Stuehr D. J., Cho H. J., Kwon N. S., Weise M. F., Nathan C. F. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7773–7777. doi: 10.1073/pnas.88.17.7773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Yui Y., Hattori R., Kosuga K., Eizawa H., Hiki K., Kawai C. Purification of nitric oxide synthase from rat macrophages. J Biol Chem. 1991 Jul 5;266(19):12544–12547. [PubMed] [Google Scholar]

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