Abstract
By administering physiological doses of interleukin-1 (IL-1) concurrently with multiple low doses of the beta cell toxin streptozotocin (MSZ), we observed an augmentation of diabetes by IL-1 in four different strains of mice. Augmentation of hyperglycemia by IL-1 was most prominent in the two MSZ-resistant mouse strains Balb/cJ and A/J. Furthermore, concurrent treatment with IL-1 and MSZ rendered these MSZ-resistant mice susceptible to the development of significant insulitis when compared to mice treated with MSZ alone. Development of insulitis was dependent upon the dose of IL-1; it was only observed at an IL-1 dose of 250 ng/kg body weight. Analysis of the leukocytic infiltrate in the islets of mice after treatment with 250 ng/kg IL-1 plus MSZ revealed the presence of L3T4+ and Lyt-2+ T lymphocytes. Administration of MSZ alone or IL-1 alone did not produce diabetes in the MSZ-resistant mice, indicating that neither of these agents was toxic to the beta cells by itself. We conclude that IL-1 synergizes with MSZ to augment diabetes in mice that are normally resistant to the diabetogenic effects of MSZ.
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- Austyn J. M., Gordon S. F4/80, a monoclonal antibody directed specifically against the mouse macrophage. Eur J Immunol. 1981 Oct;11(10):805–815. doi: 10.1002/eji.1830111013. [DOI] [PubMed] [Google Scholar]
- 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]
- Bevilacqua M. P., Pober J. S., Wheeler M. E., Cotran R. S., Gimbrone M. A., Jr Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest. 1985 Nov;76(5):2003–2011. doi: 10.1172/JCI112200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Campbell I. L., Cutri A., Wilkinson D., Boyd A. W., Harrison L. C. Intercellular adhesion molecule 1 is induced on isolated endocrine islet cells by cytokines but not by reovirus infection. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4282–4286. doi: 10.1073/pnas.86.11.4282. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Campbell I. L., Oxbrow L., Koulmanda M., Harrison L. C. IFN-gamma induces islet cell MHC antigens and enhances autoimmune, streptozotocin-induced diabetes in the mouse. J Immunol. 1988 Feb 15;140(4):1111–1116. [PubMed] [Google Scholar]
- Dinarello C. A. Interleukin-1 and its biologically related cytokines. Adv Immunol. 1989;44:153–205. doi: 10.1016/s0065-2776(08)60642-2. [DOI] [PubMed] [Google Scholar]
- Dinarello C. A., Wolff S. M. The role of interleukin-1 in disease. N Engl J Med. 1993 Jan 14;328(2):106–113. doi: 10.1056/NEJM199301143280207. [DOI] [PubMed] [Google Scholar]
- Gerling I., Chatterjee N. K. Autoantigen (64000-Mr) expression in coxsackievirus B4-induced experimental diabetes. Curr Top Microbiol Immunol. 1990;156:55–62. doi: 10.1007/978-3-642-75239-1_4. [DOI] [PubMed] [Google Scholar]
- Ginsberg-Fellner F., Witt M. E., Fedun B., Taub F., Dobersen M. J., McEvoy R. C., Cooper L. Z., Notkins A. L., Rubinstein P. Diabetes mellitus and autoimmunity in patients with the congenital rubella syndrome. Rev Infect Dis. 1985 Mar-Apr;7 (Suppl 1):S170–S176. doi: 10.1093/clinids/7.supplement_1.s170. [DOI] [PubMed] [Google Scholar]
- Higuchi Y., Herrera P., Muniesa P., Huarte J., Belin D., Ohashi P., Aichele P., Orci L., Vassalli J. D., Vassalli P. Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes. J Exp Med. 1992 Dec 1;176(6):1719–1731. doi: 10.1084/jem.176.6.1719. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jacob C. O., Aiso S., Michie S. A., McDevitt H. O., Acha-Orbea H. Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha and interleukin 1. Proc Natl Acad Sci U S A. 1990 Feb;87(3):968–972. doi: 10.1073/pnas.87.3.968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Karam J. H., Lewitt P. A., Young C. W., Nowlain R. E., Frankel B. J., Fujiya H., Freedman Z. R., Grodsky G. M. Insulinopenic diabetes after rodenticide (Vacor) ingestion: a unique model of acquired diabetes in man. Diabetes. 1980 Dec;29(12):971–978. doi: 10.2337/diab.29.12.971. [DOI] [PubMed] [Google Scholar]
- Kiesel U., Greulich B., Moumé C. M., Kolb H. Induction of experimental autoimmune diabetes by low-dose streptozotocin treatment in genetically resistant mice. Immunol Lett. 1981 Oct;3(4):227–230. doi: 10.1016/0165-2478(81)90079-1. [DOI] [PubMed] [Google Scholar]
- Kohnert K. D., Ziegler B., Fält K., Ziegler M. Augmentation of streptozotocin-induced hyperglycemia in mice by prior treatment with complete Freund's adjuvant. Int J Pancreatol. 1989 Apr;4(3):321–333. doi: 10.1007/BF02938467. [DOI] [PubMed] [Google Scholar]
- Kolb H. Mouse models of insulin dependent diabetes: low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice. Diabetes Metab Rev. 1987 Jul;3(3):751–778. doi: 10.1002/dmr.5610030308. [DOI] [PubMed] [Google Scholar]
- Like A. A., Rossini A. A. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science. 1976 Jul 30;193(4251):415–417. doi: 10.1126/science.180605. [DOI] [PubMed] [Google Scholar]
- Makino S., Kunimoto K., Muraoka Y., Mizushima Y., Katagiri K., Tochino Y. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu. 1980 Jan;29(1):1–13. doi: 10.1538/expanim1978.29.1_1. [DOI] [PubMed] [Google Scholar]
- Mandrup-Poulsen T., Bendtzen K., Nerup J., Dinarello C. A., Svenson M., Nielsen J. H. Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia. 1986 Jan;29(1):63–67. doi: 10.1007/BF02427283. [DOI] [PubMed] [Google Scholar]
- Mordes J. P., Desemone J., Rossini A. A. The BB rat. Diabetes Metab Rev. 1987 Jul;3(3):725–750. doi: 10.1002/dmr.5610030307. [DOI] [PubMed] [Google Scholar]
- Picarella D. E., Kratz A., Li C. B., Ruddle N. H., Flavell R. A. Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10036–10040. doi: 10.1073/pnas.89.21.10036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pukel C., Baquerizo H., Rabinovitch A. Destruction of rat islet cell monolayers by cytokines. Synergistic interactions of interferon-gamma, tumor necrosis factor, lymphotoxin, and interleukin 1. Diabetes. 1988 Jan;37(1):133–136. doi: 10.2337/diab.37.1.133. [DOI] [PubMed] [Google Scholar]
- RAKIETEN N., RAKIETEN M. L., NADKARNI M. V. Studies on the diabetogenic action of streptozotocin (NSC-37917). Cancer Chemother Rep. 1963 May;29:91–98. [PubMed] [Google Scholar]
- Richens E. R., Tungekar M. F., Behbehani K. Complete Freund's adjuvant has a differential amplification action on the induction of diabetes by streptozotocin in various murine strains: CFA amplifies STZ in murine diabetes. Pathology. 1987 Oct;19(4):351–357. doi: 10.3109/00313028709103882. [DOI] [PubMed] [Google Scholar]
- Rossini A. A., Appel M. C., Williams R. M., Like A. A. Genetic influence of the streptozotocin-induced insulitis and hyperglycemia. Diabetes. 1977 Oct;26(10):916–920. doi: 10.2337/diab.26.10.916. [DOI] [PubMed] [Google Scholar]
- Sarvetnick N., Liggitt D., Pitts S. L., Hansen S. E., Stewart T. A. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell. 1988 Mar 11;52(5):773–782. doi: 10.1016/0092-8674(88)90414-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Satoh J., Seino H., Abo T., Tanaka S., Shintani S., Ohta S., Tamura K., Sawai T., Nobunaga T., Oteki T. Recombinant human tumor necrosis factor alpha suppresses autoimmune diabetes in nonobese diabetic mice. J Clin Invest. 1989 Oct;84(4):1345–1348. doi: 10.1172/JCI114304. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Satoh J., Seino H., Shintani S., Tanaka S., Ohteki T., Masuda T., Nobunaga T., Toyota T. Inhibition of type 1 diabetes in BB rats with recombinant human tumor necrosis factor-alpha. J Immunol. 1990 Sep 1;145(5):1395–1399. [PubMed] [Google Scholar]
- Stewart T. A., Hultgren B., Huang X., Pitts-Meek S., Hully J., MacLachlan N. J. Induction of type I diabetes by interferon-alpha in transgenic mice. Science. 1993 Jun 25;260(5116):1942–1946. doi: 10.1126/science.8100367. [DOI] [PubMed] [Google Scholar]
- Todd J. A. Genetic control of autoimmunity in type 1 diabetes. Immunol Today. 1990 Apr;11(4):122–129. doi: 10.1016/0167-5699(90)90049-f. [DOI] [PubMed] [Google Scholar]
- Vertrees S., Wilson C. A., Ubungen R., Wilson D., Baskin D. G., Toivola B., Jacobs C., Boiani N., Baker P., Lernmark A. Interleukin-1 beta regulation of islet and thyroid autoimmunity in the BB rat. J Autoimmun. 1991 Oct;4(5):717–732. doi: 10.1016/0896-8411(91)90168-c. [DOI] [PubMed] [Google Scholar]
- Vives M., Soldevila G., Alcalde L., Lorenzo C., Somoza N., Pujol-Borrell R. Adhesion molecules in human islet beta-cells. De novo induction of ICAM-1 but not LFA-3. Diabetes. 1991 Nov;40(11):1382–1390. doi: 10.2337/diab.40.11.1382. [DOI] [PubMed] [Google Scholar]
- Wilson C. A., Jacobs C., Baker P., Baskin D. G., Dower S., Lernmark A., Toivola B., Vertrees S., Wilson D. IL-1 beta modulation of spontaneous autoimmune diabetes and thyroiditis in the BB rat. J Immunol. 1990 May 15;144(10):3784–3788. [PubMed] [Google Scholar]
- Wilson G. L., Leiter E. H. Streptozotocin interactions with pancreatic beta cells and the induction of insulin-dependent diabetes. Curr Top Microbiol Immunol. 1990;156:27–54. doi: 10.1007/978-3-642-75239-1_3. [DOI] [PubMed] [Google Scholar]


