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. 1993 Aug;93(2):273–278. doi: 10.1111/j.1365-2249.1993.tb07979.x

Protection of islet cells from inflammatory cell death in vitro.

V Burkart 1, H Kolb 1
PMCID: PMC1554829  PMID: 8348756

Abstract

Islet cells cocultured with activated macrophages are lysed within 15 h in vitro. We showed previously that nitric oxide generated by macrophages is a major mediator of islet cell death. We have now probed several pathways to interfere with the chain of events leading to islet cell death. Scavenging of extracellular oxygen radicals by superoxide dismutase and catalase did not improve islet cell survival. Scavenging of extra- and intracellular oxygen radicals by two potent substances, citiolone and dimethyl-thiourea, also did not reduce islet cell lysis, while a lipid-soluble scavenger, probucol, provided partial protection. These findings argue against a synergistic action of nitric oxide and oxygen radicals in islet cell toxicity. The inhibition of poly(ADP-ribose)polymerase by 3-aminobenzamide significantly improved islet cell survival. Selective inhibitors of cyclooxygenase, such as indomethacin or acetylsalicylic acid, did not improve islet cell survival. Full protection was seen in the presence of NDGA, an inhibitor of lipoxygenase, and partial suppression was caused by BW755c, an inhibitor of both lipoxygenase and cyclooxygenase. We conclude that inflammatory islet cell death caused by activated macrophages involves the activation of arachidonic acid metabolism and of poly(ADP-ribose)polymerase, but that scavenging of oxygen free radicals provides little protection from lysis.

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Selected References

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  1. Appels B., Burkart V., Kantwerk-Funke G., Funda J., Kolb-Bachofen V., Kolb H. Spontaneous cytotoxicity of macrophages against pancreatic islet cells. J Immunol. 1989 Jun 1;142(11):3803–3808. [PubMed] [Google Scholar]
  2. Arroyo P. L., Hatch-Pigott V., Mower H. F., Cooney R. V. Mutagenicity of nitric oxide and its inhibition by antioxidants. Mutat Res. 1992 Mar;281(3):193–202. doi: 10.1016/0165-7992(92)90008-6. [DOI] [PubMed] [Google Scholar]
  3. Babior B. M. The respiratory burst of phagocytes. J Clin Invest. 1984 Mar;73(3):599–601. doi: 10.1172/JCI111249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beckman J. S., Beckman T. W., Chen J., Marshall P. A., Freeman B. A. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620–1624. doi: 10.1073/pnas.87.4.1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fehsel K., Jalowy A., Qi S., Burkart V., Hartmann B., Kolb H. Islet cell DNA is a target of inflammatory attack by nitric oxide. Diabetes. 1993 Mar;42(3):496–500. doi: 10.2337/diab.42.3.496. [DOI] [PubMed] [Google Scholar]
  6. Gaillard T., Mülsch A., Busse R., Klein H., Decker K. Regulation of nitric oxide production by stimulated rat Kupffer cells. Pathobiology. 1991;59(4):280–283. doi: 10.1159/000163663. [DOI] [PubMed] [Google Scholar]
  7. Grankvist K., Marklund S., Täljedal I. B. Superoxide dismutase is a prophylactic against alloxan diabetes. Nature. 1981 Nov 12;294(5837):158–160. doi: 10.1038/294158a0. [DOI] [PubMed] [Google Scholar]
  8. Hanenberg H., Kolb-Bachofen V., Kantwerk-Funke G., Kolb H. Macrophage infiltration precedes and is a prerequisite for lymphocytic insulitis in pancreatic islets of pre-diabetic BB rats. Diabetologia. 1989 Feb;32(2):126–134. doi: 10.1007/BF00505185. [DOI] [PubMed] [Google Scholar]
  9. Heikkila R. E., Cabbat E. S. Protection against alloxan-induced diabetes in mice by the hydroxyl radical scavenger dimethylurea. Eur J Pharmacol. 1978 Nov 1;52(1):57–60. doi: 10.1016/0014-2999(78)90021-3. [DOI] [PubMed] [Google Scholar]
  10. Kallmann B., Burkart V., Kröncke K. D., Kolb-Bachofen V., Kolb H. Toxicity of chemically generated nitric oxide towards pancreatic islet cells can be prevented by nicotinamide. Life Sci. 1992;51(9):671–678. doi: 10.1016/0024-3205(92)90240-p. [DOI] [PubMed] [Google Scholar]
  11. Kita T., Nagano Y., Yokode M., Ishii K., Kume N., Ooshima A., Yoshida H., Kawai C. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5928–5931. doi: 10.1073/pnas.84.16.5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kolb-Bachofen V., Epstein S., Kiesel U., Kolb H. Low-dose streptozocin-induced diabetes in mice. Electron microscopy reveals single-cell insulitis before diabetes onset. Diabetes. 1988 Jan;37(1):21–27. doi: 10.2337/diab.37.1.21. [DOI] [PubMed] [Google Scholar]
  13. Kolb H., Burkart V., Appels B., Hanenberg H., Kantwerk-Funke G., Kiesel U., Funda J., Schraermeyer U., Kolb-Bachofen V. Essential contribution of macrophages to islet cell destruction in vivo and in vitro. J Autoimmun. 1990 Apr;3 (Suppl 1):117–120. doi: 10.1016/s0896-8411(09)90020-8. [DOI] [PubMed] [Google Scholar]
  14. Kröncke K. D., Funda J., Berschick B., Kolb H., Kolb-Bachofen V. Macrophage cytotoxicity towards isolated rat islet cells: neither lysis nor its protection by nicotinamide are beta-cell specific. Diabetologia. 1991 Apr;34(4):232–238. doi: 10.1007/BF00405081. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Kunkel S. L., Chensue S. W., Mouton C., Higashi G. I. Role of lipoxygenase products in murine pulmonary granuloma formation. J Clin Invest. 1984 Aug;74(2):514–524. doi: 10.1172/JCI111449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lee K. U., Amano K., Yoon J. W. Evidence for initial involvement of macrophage in development of insulitis in NOD mice. Diabetes. 1988 Jul;37(7):989–991. doi: 10.2337/diab.37.7.989. [DOI] [PubMed] [Google Scholar]
  18. Lewis B. S., Ganz W., Laramee P., Cercek B., Hod H., Shah P. K., Lew A. S. Usefulness of a rapid initial increase in plasma creatine kinase activity as a marker of reperfusion during thrombolytic therapy for acute myocardial infarction. Am J Cardiol. 1988 Jul 1;62(1):20–24. doi: 10.1016/0002-9149(88)91358-6. [DOI] [PubMed] [Google Scholar]
  19. Li Y., Severn A., Rogers M. V., Palmer R. M., Moncada S., Liew F. Y. Catalase inhibits nitric oxide synthesis and the killing of intracellular Leishmania major in murine macrophages. Eur J Immunol. 1992 Feb;22(2):441–446. doi: 10.1002/eji.1830220223. [DOI] [PubMed] [Google Scholar]
  20. Malaisse W. J., Malaisse-Lagae F., Sener A., Pipeleers D. G. Determinants of the selective toxicity of alloxan to the pancreatic B cell. Proc Natl Acad Sci U S A. 1982 Feb;79(3):927–930. doi: 10.1073/pnas.79.3.927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Marotta P., Sautebin L., Di Rosa M. Modulation of the induction of nitric oxide synthase by eicosanoids in the murine macrophage cell line J774. Br J Pharmacol. 1992 Nov;107(3):640–641. doi: 10.1111/j.1476-5381.1992.tb14499.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Papadimitriou J. M., Ashman R. B. Macrophages: current views on their differentiation, structure, and function. Ultrastruct Pathol. 1989 Jul-Aug;13(4):343–372. doi: 10.3109/01913128909048488. [DOI] [PubMed] [Google Scholar]
  23. Rankin P. W., Jacobson E. L., Benjamin R. C., Moss J., Jacobson M. K. Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo. J Biol Chem. 1989 Mar 15;264(8):4312–4317. [PubMed] [Google Scholar]
  24. Renz H., Gong J. H., Schmidt A., Nain M., Gemsa D. Release of tumor necrosis factor-alpha from macrophages. Enhancement and suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol. 1988 Oct 1;141(7):2388–2393. [PubMed] [Google Scholar]
  25. Ryoyama K., Ryoyama C. Cyclophosphamide modifies the induction kinetics but not cell types and cytotoxic mechanisms of antitumor cells elicited with OK-432 plus attenuated tumor cells. Cancer Immunol Immunother. 1991;34(3):143–149. doi: 10.1007/BF01742304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sandler S., Andersson A. The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro. Diabetologia. 1982 Oct;23(4):374–378. doi: 10.1007/BF00253747. [DOI] [PubMed] [Google Scholar]
  27. Satoh M. S., Lindahl T. Role of poly(ADP-ribose) formation in DNA repair. Nature. 1992 Mar 26;356(6367):356–358. doi: 10.1038/356356a0. [DOI] [PubMed] [Google Scholar]
  28. Schwamberger G., Flesch I., Ferber E. Tumoricidal effector molecules of murine macrophages. Pathobiology. 1991;59(4):248–253. doi: 10.1159/000163656. [DOI] [PubMed] [Google Scholar]
  29. Sestili P., Spadoni G., Balsamini C., Scovassi I., Cattabeni F., Duranti E., Cantoni O., Higgins D., Thomson C. Structural requirements for inhibitors of poly(ADP-ribose) polymerase. J Cancer Res Clin Oncol. 1990;116(6):615–622. doi: 10.1007/BF01637083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shimizu H., Uehara Y., Shimomura Y., Tanaka Y., Kobayashi I. Probucol attenuated hyperglycemia in multiple low-dose streptozotocin-induced diabetic mice. Life Sci. 1991;49(18):1331–1338. doi: 10.1016/0024-3205(91)90197-j. [DOI] [PubMed] [Google Scholar]
  31. Spragg R. G. DNA strand break formation following exposure of bovine pulmonary artery and aortic endothelial cells to reactive oxygen products. Am J Respir Cell Mol Biol. 1991 Jan;4(1):4–10. doi: 10.1165/ajrcmb/4.1.4. [DOI] [PubMed] [Google Scholar]
  32. Sumoski W., Baquerizo H., Rabinovitch A. Oxygen free radical scavengers protect rat islet cells from damage by cytokines. Diabetologia. 1989 Nov;32(11):792–796. doi: 10.1007/BF00264909. [DOI] [PubMed] [Google Scholar]
  33. Uchigata Y., Yamamoto H., Kawamura A., Okamoto H. Protection by superoxide dismutase, catalase, and poly(ADP-ribose) synthetase inhibitors against alloxan- and streptozotocin-induced islet DNA strand breaks and against the inhibition of proinsulin synthesis. J Biol Chem. 1982 Jun 10;257(11):6084–6088. [PubMed] [Google Scholar]
  34. Uchigata Y., Yamamoto H., Nagai H., Okamoto H. Effect of poly(ADP-ribose) synthetase inhibitor administration to rats before and after injection of alloxan and streptozotocin on islet proinsulin synthesis. Diabetes. 1983 Apr;32(4):316–318. doi: 10.2337/diab.32.4.316. [DOI] [PubMed] [Google Scholar]
  35. Vane J. R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971 Jun 23;231(25):232–235. doi: 10.1038/newbio231232a0. [DOI] [PubMed] [Google Scholar]
  36. Villa M. L., Valenti F., Mantovani M. Modulation of natural killing by cyclo- and lipo-oxygenase inhibitors. Immunology. 1988 Jan;63(1):93–97. [PMC free article] [PubMed] [Google Scholar]
  37. Yamada K., Nonaka K., Hanafusa T., Miyazaki A., Toyoshima H., Tarui S. Preventive and therapeutic effects of large-dose nicotinamide injections on diabetes associated with insulitis. An observation in nonobese diabetic (NOD) mice. Diabetes. 1982 Sep;31(9):749–753. doi: 10.2337/diab.31.9.749. [DOI] [PubMed] [Google Scholar]
  38. Yonemura Y., Takashima T., Miwa K., Miyazaki I., Yamamoto H., Okamoto H. Amelioration of diabetes mellitus in partially depancreatized rats by poly(ADP-ribose) synthetase inhibitors. Evidence of islet B-cell regeneration. Diabetes. 1984 Apr;33(4):401–404. doi: 10.2337/diab.33.4.401. [DOI] [PubMed] [Google Scholar]
  39. Yoshino G., Matsushita M., Maeda E., Morita M., Nagata K., Matsuba K., Tani T., Horinuki R., Kimura Y., Kazumi T. Effect of probucol on recovery from streptozotocin diabetes in rats. Horm Metab Res. 1992 Jul;24(7):306–309. doi: 10.1055/s-2007-1003319. [DOI] [PubMed] [Google Scholar]

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