Summary
The monokines interleukin-1α and -β have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1β, and on interleukin-1β induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1β on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100–1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1βon rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1β-induced inhibition of insulin release after 24 h. In contrast, interleukin-1β-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1β stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1β effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist. An anti-mouse interleukin-1 receptor type I antibody completely abolished interleukin-1β effects on isolated mouse islets. A 10–100-fold molar excess of interleukin-1 receptor antagonist antagonised interleukin-1β-induced fever, hypercorticosteronaemia and hyperglucagonaemia, but not interleukin-1β-induced reduction in insulin/glucose ratio in normal rats. In conclusion, our results suggest that antagonism of interleukin-1β effects on beta cells requires higher concentrations of interleukin-1 receptor antagonist than those necessary to block interleukin-1 action on islet alpha cells and other interleukin-1 targets in vitro and in vivo. This may contribute to the understanding of the specificity of the immunological beta-cell destruction leading to insulin-dependent diabetes.
Article PDF
Similar content being viewed by others
References
Mandrup-Poulsen T, Egeberg J, Nerup J, Bendtzen K, Nielsen JH, Dinarello CA (1987) Ultrastructural studies of time-course and cellular specificity of interleukin-1 mediated islet cytotoxicity. Acta Path Microbiol Immunol Scand 95: C55-C63
Sandler S, Bendtzen K, Borg LAH, Eizirik DL, Strandell E, Welsh N (1989) Studies on the mechanisms causing inhibition of insulin secretion in rat pancreatic islets exposed to human interleukin-1β indicate a perturbation in the mitochondrial function. Endocrinology 124: 1492–1501
Helqvist S, Zumsteg UW, Spinas GA et al. (1991) Repetitive exposure of pancreatic islets to interleukin-1β. An in vitro model of pre-diabetes? Autoimmunity 10: 311–318
Wogensen LD, Kolb-Bachofen V, Christensen P et al. (1990) Functional and morphological effects of interleukin-1β on the perfused rat pancreas. Diabetologia 33: 15–23
McDaniel ML, Hughes JH, Wolf BA, Easom RA, Turk JW (1988) Description and mechanistic consideration of interleukin-1 and insulin secretion. Diabetes 37: 1311–1315
Mandrup-Poulsen T, Helqvist S, Mølvig J, Wogensen LD, Nerup J (1989) Cytokines as immune effector molecules in autoimmune endocrine diseases with special reference to insulin-dependent diabetes mellitus. Autoimmunity 4: 191–218
Sandler S, Eizirik DL, Svensson C, Strandell E, Welsh M, Welsh N (1991) Biochemical and molecular actions of interleukin-1 on pancreatic β-cells. Autoimmunity 10: 241–253
Jiang Z, Woda BA (1991) Cytokine gene expression in the islets of the diabetic Biobreeding/Worcester rat. J Immunol 146: 2990–2994
Held W, MacDonald HR, Weissman IL, Hess MW, Mueller C (1990) Genes encoding tumor necrosis factor α and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci USA 87: 2239–2243
Wogensen L, Reimers J, Nerup J et al. (1992) Repetitive in vivo treatment with human recombinant interleukin-1β modifies beta-cell function in normal rats. Diabetologia 35: 331–339
Dinarello CA (1991) Interleukin-1 and interleukin-1 antagonism. Blood 77: 1627–1652
McMahan CJ, Slack JL, Mosley B et al. (1991) A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J 10: 2821–2832
Benjamin D, Dower SK (1990) Human B cells express two types of interleukin-1 receptors. Blood 75: 2017–2023
Deyerle KL, Sims JE, Dower SK, Bothwell MA (1992) Pattern of IL-1 receptor gene expression suggests role in noninflammatory processes. J Immunol 149: 1657–1665
Hammonds P, Beggs M, Beresford G, Espinal J, Clarke J, Mertz RJ (1990) Insulin-secreting β-cells possess specific receptors for interleukin-1β. FEBS Lett 261: 97–100
Eizirik DL, Björklund A, Welsh N (1993) 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 317: 62–66
Belavoine JF, De Rochemonteix B, Williamson K, Seckinger P, Cruchaud A, Dayer JM (1987) Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urinederived human interleukin 1 and inhibitor(s). J Clin Invest 78: 1120–1124
Arend WP, Joslin FG, Massoni PJ (1985) Effects of immune complexes on production by human monocytes of interleukin 1 or an interleukin 1 inhibitor. J Immunol 134: 3868–3875
Seckinger P, Lowenthal JW, Williamson K, Dayer J-M, MacDonald R (1987) A urine inhibitor of interleukin 1 activity that blocks ligand binding. J Immunol 139: 1546–1549
Eisenberg SP, Evans RJ, Arend WP et al. (1990) Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature 343: 341–346
Carter DB, Deibel MR Jr, Dunn CJ et al. (1990) Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature 344: 633–638
Granowitz EV, Clark BD, Mancilla J, Dinarello CA (1991) Interleukin-1 receptor antagonist competitively inhibits the binding of interleukin-1 to the type II interleukin-1 receptor. J Biol Chem 266: 14147–14150
Dinarello CA, Thompson RC (1991) Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunology Today 12: 404–410
Dayer-Metroz M-D, Wollheim CB, Seckinger P, Dayer J-M (1989) A natural interleukin 1 (IL-1) inhibitor counteracts the inhibitory effect of IL-1 on insulin production in cultured rat pancreatic islets. J Autoimmunity 2: 163–171
Eizirik DL, Tracey DE, Bendtzen K, Sandler S (1991) An interleukin-1 receptor antagonist protein protects insulin-producing beta cells against suppressive effects of interleukin-1β. Diabetologia 34: 445–448
Dalbøge H, Bayne S, Christensen T, Hejnass KR (1989) Cloning and expression of an interleukin-1β precursor and its conversion to interleukin-1β. FEBS Lett 246: 89–93
Hejnæs KR, Sehested B, Worsaae H, Mølvig J, Wollmer A (1990) The effect of N-terminal extension on the structure and function of human interleukin-1β. Biol Chem Hoppe-Seylor 371: 23–30
Chizzonite R, Truitt T, Kilian PL et al. (1989) Two high-affinity interleukin 1 receptors represent separate gene products. Proc Natl Acad Sci USA 86: 8029–8033
Bomsztyk K, Sims JE, Stanton TH et al. (1989) Evidence for different interleukin 1 receptors in murine Band T-cell lines. Proc Natl Acad Sci USA 86: 8034–8038
McIntyre KW, Stepan GJ, Kolinsky KD et al. (1991) Inhibition of Interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med 173: 931–939
Mølvig J, Baek L, Christensen P et al. (1988) Endotoxin-stimulated human monocyte secretion of interleukin 1, tumour necrosis factor alpha, and prostaglandin E2 shows stable interindividual differences. Scand J Immunol 27: 705–716
Brunstedt J, Nielsen JH, Lernmark Å, Hagedorn Study Group (1984) Isolation of islets from mice and rats. In: Larner J, Pohl SL (eds) Methods in diabetes research laboratory methods. Vol 1, pt. C. Wiley, New York, pp 254–258
Spinas GA, Hansen BS, Linde S et al. (1987) Interleukin 1 dosedependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans. Diabetologia 30: 474–480
Mandrup-Poulsen T, Spinas GA, Prowse SJ et al. (1987) Islet cytotoxicity of interleukin-1: influence of culture conditions and islet donor characteristics. Diabetes 36: 641–647
Tzakis AG, Ricordi C, Alejandro R et al. (1990) Pancreatic islet transplantation after upper abdominal exenteration and liver replacement. Lancet 336: 402–405
Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW (1988) Automated method for isolation of human pancreatic islets. Diabetes 37: 413–420
London NJM, Contractor H, Lake SP, Aucott GC, Bell PRF, James RFL (1989) A microflurometric viability assay for isolated human and rat islets of Langerhans. Diabetes Res 12: 141–149
Heding LG (1972) Determination of total serum insulin (IRI) in insulin-treated diabetic patients. Diabetologia 8: 260–266
Arend WP, Joslin FG, Thompson RC, Hannum CH (1989) An IL-1 inhibitor from human monocytes. Production and characterization of biologic properties. J Immunol 143: 1851–1858
Arend WP, Welgus HG, Thompson RC, Eisenberg SP (1990) Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest 85: 1694–1697
Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP (1991) Interleukin-1 (IL-1) receptor antagonist binds to the 80-KDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266: 10331–10336
Ikejima T, Zhang X, Dinarello CA (1991) IL-1 receptor antagonist (IL-1 ra) reduces IL-1-mediated fever in the rabbit but not LPS or staphylococcus epidermidis-induced fever. Clin Res 39: 462A (Abstract)
Ohlsson K, Björk P, Bergenfeldt M, Hageman R, Thompson RC (1990) Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 348: 550–552
Opp MR, Krueger JM (1991) Interleukin 1-receptor antagonist blocks interleukin 1-induced sleep and fever. Am J Physiol 260: R453-R457
Campbell IL, Iscaro A, Harrison LC (1988) IFN-γand tumor necrosis factor-α. Cytotoxicity to murine islets of Langerhans. J Immunol 141: 2325–2329
Pukel C, Baqurizo H, Rabinovitch A (1988) Destruction of rat islet cell monolayers by cytokines. Synergistic interactions of interferon-gamma, tumor necrosis factor, lymphotoxin, and interleukin 1. Diabetes 37: 133–136
Dayer-Metroz M-D, Duhamel D, Rufer N at al. (1992) IL-1 receptor antagonist delays spontaneous autoimmune diabetes in BB rats. Eur J Clin Invest 22: A50 (Abstract)
Eizirik DL, Tracey DE, Bendtzen K, Sandler S (1992) Role of receptor binding and gene transcription for both the stimulatory and inhibitory effects of interleukin-1 in pancreatic β-cells. Autoimmunity 12: 127–133
Mancilla J, Ikejima I, Clark BD, Orencole SF, Sirko S, Dinarello CA (1989) Lectin binding suggests different glycosylation patterns of IL-1 receptors on different cells. Cytokine 1: 95 (Abstract)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zumsteg, U., Reimers, J.I., Pociot, F. et al. Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats. Diabetologia 36, 759–766 (1993). https://doi.org/10.1007/BF00401148
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00401148