Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1994 May 1;299(Pt 3):719–724. doi: 10.1042/bj2990719

Reversibility of interleukin-1 beta-induced islet destruction and dysfunction by the inhibition of nitric oxide synthase.

J A Corbett 1, M L McDaniel 1
PMCID: PMC1138079  PMID: 7514870

Abstract

We have examined the reversibility of NO-mediated islet dysfunction and destruction induced by interleukin-1 beta (IL-1 beta). Previous studies have shown that pretreatment of islets for 18 h with IL-1 beta results in an inhibition of glucose-stimulated insulin secretion that requires 4 days incubation in the absence of IL-1 beta to restore islet secretory function. In this study we use a sequential experimental design in which islets are first exposed to IL-1 beta for 18 h, and then treated with the NO synthase inhibitor NG-monomethyl-L-arginine (NMMA). Insulin secretion is inhibited by 98% after the 18 h incubation with IL-1 beta, and this inhibition is reversed in a time-dependent fashion by NMMA, with complete recovery of insulin secretion observed 8 h after the inhibition of NO synthase. Inhibition of NO synthase also restores IL-1 beta-induced inhibition of mitochondrial aconitase activity in a time-dependent fashion that mimics the recovery of glucose-stimulated insulin secretion by islets. Ferrous iron and the reducing agents cysteine and thiosulphate accelerate the rate of recovery of insulin secretion, and ferrous iron and thiosulphate stimulate the recovery of islet aconitase activity, suggesting that iron-sulphurcentre reconstitution may be involved in the recovery process. The recovery process also appears to require mRNA transcription, because the transcriptional inhibitor actinomycin D prevents the recovery of insulin secretion by islets after the inhibition of NO synthase. Although IL-1 beta induces the co-expression of NO synthase and cyclo-oxygenase by islets, cyclo-oxygenase is not involved in the recovery of glucose-stimulated insulin secretion. Inhibition of NO synthase also prevents IL-1 beta-induced islet destruction, which otherwise occurs during a 96 h continuous exposure to this cytokine. The destructive effects of IL-1 beta on islet viability are prevented if NMMA is added to islet cultures during the first 24 h of exposure to IL-1 beta, but islet destruction is not prevented if NMMA is added after the first 48 h exposure to IL-1 beta. These results show that IL-1 beta-induced islet dysfunction is reversed by the inhibition of NO synthase, that recovery of insulin secretion is stimulated by iron and reducing agents, and that the recovery process appears to require mRNA transcription. We also show that it is possible to rescue islets from the destructive effects of IL-1 beta if NO synthase is inhibited early after its induction.

Full text

PDF
719

Images in this article

722Figure 3
on p.722

Selected References

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

  1. Bendtzen K., Mandrup-Poulsen T., Nerup J., Nielsen J. H., Dinarello C. A., Svenson M. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science. 1986 Jun 20;232(4757):1545–1547. doi: 10.1126/science.3086977. [DOI] [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., Kwon G., Turk J., McDaniel M. L. IL-1 beta induces the coexpression of both nitric oxide synthase and cyclooxygenase by islets of Langerhans: activation of cyclooxygenase by nitric oxide. Biochemistry. 1993 Dec 21;32(50):13767–13770. doi: 10.1021/bi00213a002. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Corbett J. A., McDaniel M. L. Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM. Diabetes. 1992 Aug;41(8):897–903. doi: 10.2337/diab.41.8.897. [DOI] [PubMed] [Google Scholar]
  6. Corbett J. A., Sweetland M. A., Wang J. L., Lancaster J. R., Jr, McDaniel M. L. Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1731–1735. doi: 10.1073/pnas.90.5.1731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Corbett J. A., Tilton R. G., Chang K., Hasan K. S., Ido Y., Wang J. L., Sweetland M. A., Lancaster J. R., Jr, Williamson J. R., McDaniel M. L. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes. 1992 Apr;41(4):552–556. doi: 10.2337/diab.41.4.552. [DOI] [PubMed] [Google Scholar]
  8. Corbett J. A., Wang J. L., Hughes J. H., Wolf B. A., Sweetland M. A., Lancaster J. R., Jr, McDaniel M. L. 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. Biochem J. 1992 Oct 1;287(Pt 1):229–235. doi: 10.1042/bj2870229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Corbett J. A., Wang J. L., Misko T. P., Zhao W., Hickey W. F., McDaniel M. L. Nitric oxide mediates IL-1 beta-induced islet dysfunction and destruction: prevention by dexamethasone. Autoimmunity. 1993;15(2):145–153. doi: 10.3109/08916939309043889. [DOI] [PubMed] [Google Scholar]
  10. Corbett J. A., Wang J. L., Sweetland M. A., Lancaster J. R., Jr, McDaniel M. L. Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide. J Clin Invest. 1992 Dec;90(6):2384–2391. doi: 10.1172/JCI116129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dimmeler S., Ankarcrona M., Nicotera P., Brüne B. Exogenous nitric oxide (NO) generation or IL-1 beta-induced intracellular NO production stimulates inhibitory auto-ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase in RINm5F cells. J Immunol. 1993 Apr 1;150(7):2964–2971. [PubMed] [Google Scholar]
  12. Drapier J. C., Hibbs J. B., Jr Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J Immunol. 1988 Apr 15;140(8):2829–2838. [PubMed] [Google Scholar]
  13. 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]
  14. Drapier J. C., Hirling H., Wietzerbin J., Kaldy P., Kühn L. C. Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J. 1993 Sep;12(9):3643–3649. doi: 10.1002/j.1460-2075.1993.tb06038.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Eizirik D. L., Björklund A., Welsh N. Interleukin-1-induced expression of nitric oxide synthase in insulin-producing cells is preceded by c-fos induction and depends on gene transcription and protein synthesis. FEBS Lett. 1993 Feb 8;317(1-2):62–66. doi: 10.1016/0014-5793(93)81492-i. [DOI] [PubMed] [Google Scholar]
  17. Eizirik D. L., Cagliero E., Björklund A., Welsh N. Interleukin-1 beta induces the expression of an isoform of nitric oxide synthase in insulin-producing cells, which is similar to that observed in activated macrophages. FEBS Lett. 1992 Aug 24;308(3):249–252. doi: 10.1016/0014-5793(92)81285-t. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. 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]
  20. Henry Y., Ducrocq C., Drapier J. C., Servent D., Pellat C., Guissani A. Nitric oxide, a biological effector. Electron paramagnetic resonance detection of nitrosyl-iron-protein complexes in whole cells. Eur Biophys J. 1991;20(1):1–15. doi: 10.1007/BF00183275. [DOI] [PubMed] [Google Scholar]
  21. Hughes J. H., Easom R. A., Wolf B. A., Turk J., McDaniel M. L. Interleukin 1-induced prostaglandin E2 accumulation by isolated pancreatic islets. Diabetes. 1989 Oct;38(10):1251–1257. doi: 10.2337/diab.38.10.1251. [DOI] [PubMed] [Google Scholar]
  22. Kolb H., Kolb-Bachofen V. Type 1 (insulin-dependent) diabetes mellitus and nitric oxide. Diabetologia. 1992 Aug;35(8):796–797. doi: 10.1007/BF00429103. [DOI] [PubMed] [Google Scholar]
  23. Kröncke K. D., Kolb-Bachofen V., Berschick B., Burkart V., Kolb H. Activated macrophages kill pancreatic syngeneic islet cells via arginine-dependent nitric oxide generation. Biochem Biophys Res Commun. 1991 Mar 29;175(3):752–758. doi: 10.1016/0006-291x(91)91630-u. [DOI] [PubMed] [Google Scholar]
  24. Lacy P. E., Finke E. H. Activation of intraislet lymphoid cells causes destruction of islet cells. Am J Pathol. 1991 May;138(5):1183–1190. [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Mandrup-Poulsen T., Bendtzen K., Nerup J., Egeberg J., Nielsen J. H. Mechanisms of pancreatic islet cell destruction. Dose-dependent cytotoxic effect of soluble blood mononuclear cell mediators on isolated islets of Langerhans. Allergy. 1986 May;41(4):250–259. doi: 10.1111/j.1398-9995.1986.tb02025.x. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Palmer J. P., Helqvist S., Spinas G. A., Mølvig J., Mandrup-Poulsen T., Andersen H. U., Nerup J. Interaction of beta-cell activity and IL-1 concentration and exposure time in isolated rat islets of Langerhans. Diabetes. 1989 Oct;38(10):1211–1216. doi: 10.2337/diab.38.10.1211. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Reif D. W., Simmons R. D. Nitric oxide mediates iron release from ferritin. Arch Biochem Biophys. 1990 Dec;283(2):537–541. doi: 10.1016/0003-9861(90)90680-w. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. 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]
  34. Stadler J., Curran R. D., Ochoa J. B., Harbrecht B. G., Hoffman R. A., Simmons R. L., Billiar T. R. Effect of endogenous nitric oxide on mitochondrial respiration of rat hepatocytes in vitro and in vivo. Arch Surg. 1991 Feb;126(2):186–191. doi: 10.1001/archsurg.1991.01410260074010. [DOI] [PubMed] [Google Scholar]
  35. Weiss G., Goossen B., Doppler W., Fuchs D., Pantopoulos K., Werner-Felmayer G., Wachter H., Hentze M. W. Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway. EMBO J. 1993 Sep;12(9):3651–3657. doi: 10.1002/j.1460-2075.1993.tb06039.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Welsh N., Eizirik D. L., Bendtzen K., Sandler S. 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. Endocrinology. 1991 Dec;129(6):3167–3173. doi: 10.1210/endo-129-6-3167. [DOI] [PubMed] [Google Scholar]
  37. Wright P. H., Makulu D. R., Vichick D., Sussman K. E. Insulin immunoassay by back-titration; some characteristics of the technic and the insulin precipitant action of alcohol. Diabetes. 1971 Jan;20(1):33–45. doi: 10.2337/diab.20.1.33. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES