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. 1999;8(2):85–91. doi: 10.1080/09629359990577

The destructive action of IL-1alpha and IL-1beta in IDDM is a multistage process: evidence and confirmation by apoptotic studies, induction of intermediates and electron microscopy.

S Vassiliadis 1, V Dragiotis 1, E Protopapadakis 1, I Athanassakis 1, P Mitlianga 1, K Konidaris 1, G K Papadopoulos 1
PMCID: PMC1781784  PMID: 10704145

Abstract

Using the rat beta-cell RIN-5AH insulinoma line as a means for studying insulin-dependent diabetes mellitus (IDDM), it is shown that interleukin-1 (IL-1) induces beta-cell damage initiated by early apoptotic signals. This action is demonstrated by DNA fragmentation, as assessed by specific BrdU labeling, surface expression of Fas and nitric oxide (NO) production. In addition, the interplay between NO and Fas is shown, while scanning electron microscopy (SEM) confirms apoptosis by revealing the degree and type of cellular damage which, in the case of IL-1alpha, can be reversed by an inhibitor to NO synthesis. Apoptosis is also reconfirmed by transmission electron microscopy (TEM) by observing condensed nuclear chromatin after IL-1 exposure. Thus, treatment of insulinoma cells with IL-1alpha and IL-1beta seems to initiate a number of signals, including PKC activation as published previously, that ultimately lead to beta-cell destruction. Each IL-1 isoform, however, definitely follows a different pathway of action.

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Selected References

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  1. Atkinson M. A., Maclaren N. K. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med. 1994 Nov 24;331(21):1428–1436. doi: 10.1056/NEJM199411243312107. [DOI] [PubMed] [Google Scholar]
  2. Benoist C., Mathis D. Cell death mediators in autoimmune diabetes--no shortage of suspects. Cell. 1997 Apr 4;89(1):1–3. doi: 10.1016/s0092-8674(00)80174-9. [DOI] [PubMed] [Google Scholar]
  3. Cahill G. F., Jr, McDevitt H. O. Insulin-dependent diabetes mellitus: the initial lesion. N Engl J Med. 1981 Jun 11;304(24):1454–1465. doi: 10.1056/NEJM198106113042403. [DOI] [PubMed] [Google Scholar]
  4. Castaño L., Eisenbarth G. S. Type-I diabetes: a chronic autoimmune disease of human, mouse, and rat. Annu Rev Immunol. 1990;8:647–679. doi: 10.1146/annurev.iy.08.040190.003243. [DOI] [PubMed] [Google Scholar]
  5. Chervonsky A. V., Wang Y., Wong F. S., Visintin I., Flavell R. A., Janeway C. A., Jr, Matis L. A. The role of Fas in autoimmune diabetes. Cell. 1997 Apr 4;89(1):17–24. doi: 10.1016/s0092-8674(00)80178-6. [DOI] [PubMed] [Google Scholar]
  6. Chick W. L., Warren S., Chute R. N., Like A. A., Lauris V., Kitchen K. C. A transplantable insulinoma in the rat. Proc Natl Acad Sci U S A. 1977 Feb;74(2):628–632. doi: 10.1073/pnas.74.2.628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. 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]
  9. Eizirik D. L., Flodström M., Karlsen A. E., Welsh N. The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells. Diabetologia. 1996 Aug;39(8):875–890. doi: 10.1007/BF00403906. [DOI] [PubMed] [Google Scholar]
  10. Fang M., Zhang H. Q., Xue S. B. [Apoptosis of HL-60 cells induced by Harringtonine: membrane blebs, nucleus blebs and chromatin condensation]. Shi Yan Sheng Wu Xue Bao. 1996 Sep;29(3):221–233. [PubMed] [Google Scholar]
  11. Gazdar A. F., Chick W. L., Oie H. K., Sims H. L., King D. L., Weir G. C., Lauris V. Continuous, clonal, insulin- and somatostatin-secreting cell lines established from a transplantable rat islet cell tumor. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3519–3523. doi: 10.1073/pnas.77.6.3519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gepts W., In't Veld P. A. Islet morphologic changes. Diabetes Metab Rev. 1987 Oct;3(4):859–872. doi: 10.1002/dmr.5610030403. [DOI] [PubMed] [Google Scholar]
  13. Jackson R. A., Morris M. A., Haynes B. F., Eisenbarth G. S. Increased circulating Ia-antigen-bearing T cells in type I diabetes mellitus. N Engl J Med. 1982 Apr 1;306(13):785–788. doi: 10.1056/NEJM198204013061305. [DOI] [PubMed] [Google Scholar]
  14. Liu X., Li P., Widlak P., Zou H., Luo X., Garrard W. T., Wang X. The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8461–8466. doi: 10.1073/pnas.95.15.8461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mandrup-Poulsen T., Bendtzen K., Dinarello C. A., Nerup J. Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic beta-cell cytotoxicity. J Immunol. 1987 Dec 15;139(12):4077–4082. [PubMed] [Google Scholar]
  16. Mandrup-Poulsen T., Bendtzen K., Nielsen J. H., Bendixen G., Nerup J. Cytokines cause functional and structural damage to isolated islets of Langerhans. Allergy. 1985 Aug;40(6):424–429. doi: 10.1111/j.1398-9995.1985.tb02681.x. [DOI] [PubMed] [Google Scholar]
  17. Mandrup-Poulsen T., Egeberg J., Nerup J., Bendtzen K., Nielsen J. H., Dinarello C. A. Ultrastructural studies of time-course and cellular specificity of interleukin-1 mediated islet cytotoxicity. Acta Pathol Microbiol Immunol Scand C. 1987 Apr;95(2):55–63. doi: 10.1111/j.1699-0463.1987.tb00009.x. [DOI] [PubMed] [Google Scholar]
  18. Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia. 1996 Sep;39(9):1005–1029. doi: 10.1007/BF00400649. [DOI] [PubMed] [Google Scholar]
  19. Mauricio D., Mandrup-Poulsen T. Apoptosis and the pathogenesis of IDDM: a question of life and death. Diabetes. 1998 Oct;47(10):1537–1543. doi: 10.2337/diabetes.47.10.1537. [DOI] [PubMed] [Google Scholar]
  20. McDaniel M. L., Hughes J. H., Wolf B. A., Easom R. A., Turk J. W. Descriptive and mechanistic considerations of interleukin 1 and insulin secretion. Diabetes. 1988 Oct;37(10):1311–1315. doi: 10.2337/diab.37.10.1311. [DOI] [PubMed] [Google Scholar]
  21. Misko T. P., Moore W. M., Kasten T. P., Nickols G. A., Corbett J. A., Tilton R. G., McDaniel M. L., Williamson J. R., Currie M. G. Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol. 1993 Mar 16;233(1):119–125. doi: 10.1016/0014-2999(93)90357-n. [DOI] [PubMed] [Google Scholar]
  22. Rees D. D., Palmer R. M., Schulz R., Hodson H. F., Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol. 1990 Nov;101(3):746–752. doi: 10.1111/j.1476-5381.1990.tb14151.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Renvoizé C., Biola A., Pallardy M., Bréard J. Apoptosis: identification of dying cells. Cell Biol Toxicol. 1998 Mar;14(2):111–120. doi: 10.1023/a:1007429904664. [DOI] [PubMed] [Google Scholar]
  24. Stassi G., De Maria R., Trucco G., Rudert W., Testi R., Galluzzo A., Giordano C., Trucco M. Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus. J Exp Med. 1997 Oct 20;186(8):1193–1200. doi: 10.1084/jem.186.8.1193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Varey A. M., Lydyard P. M., Dean B. M., Van der Meide P. H., Baird J. D., Cooke A. Interferon-gamma induces class II MHC antigens on RINm5F cells. Diabetes. 1988 Feb;37(2):209–212. doi: 10.2337/diab.37.2.209. [DOI] [PubMed] [Google Scholar]
  26. Vassiliadis S., Soteriadou K. P., Papadopoulos G. K. IL-1 beta transduces different signals than IL-1 alpha leading to class II antigen expression on beta-insulinoma RIN-5AH cells through specific receptors. J Recept Signal Transduct Res. 1997 Jan-May;17(1-3):211–225. doi: 10.3109/10799899709036605. [DOI] [PubMed] [Google Scholar]
  27. Wang R., Zhang L., Yin D., Mufson R. A., Shi Y. Protein kinase C regulates Fas (CD95/APO-1) expression. J Immunol. 1998 Sep 1;161(5):2201–2207. [PubMed] [Google Scholar]
  28. Welsh N., Eizirik D. L., Sandler S. Nitric oxide and pancreatic beta-cell destruction in insulin dependent diabetes mellitus: don't take NO for an answer. Autoimmunity. 1994;18(4):285–290. doi: 10.3109/08916939409009530. [DOI] [PubMed] [Google Scholar]

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