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. 1990 Sep;86(3):856–863. doi: 10.1172/JCI114785

Interleukin 1 inhibits insulin secretion from isolated rat pancreatic islets by a process that requires gene transcription and mRNA translation.

J H Hughes 1, J R Colca 1, R A Easom 1, J Turk 1, M L McDaniel 1
PMCID: PMC296803  PMID: 2203826

Abstract

Recombinant human IL 1 beta inhibits glucose-induced insulin secretion from isolated pancreatic islets and from purified beta-cells obtained by fluorescence-activated cell sorting (FACS) of dispersed islet cells. Brief (1 h) exposure of isolated islets to IL 1 produces sustained inhibition of insulin secretion for at least 17 h after the IL 1 has been removed from the culture medium. An inhibitory effect of IL 1 on insulin secretion is not observed when islets are coincubated with an inhibitor of DNA transcription (actinomycin D). This finding indicates that the inhibitory effect of IL 1 on insulin secretion requires transcription of one or more genes during the first hour of exposure of islets to IL 1. The inhibitory effect of IL 1 on insulin secretion also requires mRNA translation, because three structurally distinct inhibitors of protein synthesis (cycloheximide, anisomycin, and puromycin) prevent IL 1-induced inhibition of insulin secretion when added to islets after the 1-h exposure to IL 1. Two-dimensional gel electrophoresis of islet proteins metabolically labeled with [35S]methionine demonstrates that IL 1 augments the expression of a 65-kD (pl approximately 6.5) protein by greater than 2.5-fold. These findings indicate that biochemical events occurring within 1 h of exposure of islets to IL 1 lead to an inhibition of insulin secretion that persists for at least 17 h after the removal of IL 1. One of the early biochemical effects of IL 1 on islets is gene transcription (0-1 h), which is followed by mRNA translation (after 1 h). Our results suggest that the inhibitory effect of IL 1 on insulin secretion is mediated by protein(s) whose synthesis is induced by IL 1.

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Selected References

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  1. Anderson N. L., Anderson N. G. Analytical techniques for cell fractions. XXII. Two-dimensional analysis of serum and tissue proteins: multiple gradient-slab gel electrophoresis. Anal Biochem. 1978 Apr;85(2):341–354. doi: 10.1016/0003-2697(78)90230-0. [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. Dayer-Métroz M. D., Wollheim C. B., Seckinger P., Dayer J. M. A natural interleukin 1 (IL-1) inhibitor counteracts the inhibitory effect of IL-1 on insulin production in cultured rat pancreatic islets. J Autoimmun. 1989 Apr;2(2):163–171. doi: 10.1016/0896-8411(89)90152-2. [DOI] [PubMed] [Google Scholar]
  4. Dinarello C. A., Wolff S. M. Molecular basis of fever in humans. Am J Med. 1982 May;72(5):799–819. doi: 10.1016/0002-9343(82)90548-4. [DOI] [PubMed] [Google Scholar]
  5. Garrels J. I. Quantitative two-dimensional gel electrophoresis of proteins. Methods Enzymol. 1983;100:411–423. doi: 10.1016/0076-6879(83)00070-1. [DOI] [PubMed] [Google Scholar]
  6. Gery I., Gershon R. K., Waksman B. H. Potentiation of the T-lymphocyte response to mitogens. I. The responding cell. J Exp Med. 1972 Jul 1;136(1):128–142. doi: 10.1084/jem.136.1.128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hammonds P., Beggs M., Beresford G., Espinal J., Clarke J., Mertz R. J. Insulin-secreting beta-cells possess specific receptors for interleukin-1 beta. FEBS Lett. 1990 Feb 12;261(1):97–100. doi: 10.1016/0014-5793(90)80645-y. [DOI] [PubMed] [Google Scholar]
  8. Helqvist S., Sehested Hansen B., Johannesen J., Ullits Andersen H., Hoiriis Nielsen J., Nerup J. Interleukin 1 induces new protein formation in isolated rat islets of Langerhans. Acta Endocrinol (Copenh) 1989 Jul;121(1):136–140. doi: 10.1530/acta.0.1210136. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Kampschmidt R. F., Upchurch H. F., Eddington C. L., Pulliam L. A. Multiple biological activities of a partially purified leukocytic endogenous mediator. Am J Physiol. 1973 Mar;224(3):530–533. doi: 10.1152/ajplegacy.1973.224.3.530. [DOI] [PubMed] [Google Scholar]
  11. Koranyi L., Permutt M. A., Chirgwin J. M., Giddings S. J. Proinsulin I and II gene expression in inbred mouse strains. Mol Endocrinol. 1989 Nov;3(11):1895–1902. doi: 10.1210/mend-3-11-1895. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. Nerup J., Mandrup-Poulsen T., Mølvig J. The HLA-IDDM association: implications for etiology and pathogenesis of IDDM. Diabetes Metab Rev. 1987 Jul;3(3):779–802. doi: 10.1002/dmr.5610030309. [DOI] [PubMed] [Google Scholar]
  18. Orland M. J., Chyn R., Permutt M. A. Modulation of proinsulin messenger RNA after partial pancreatectomy in rats. Relationships to glucose homeostasis. J Clin Invest. 1985 Jun;75(6):2047–2055. doi: 10.1172/JCI111924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Rabinovitch A., Pukel C., Baquerizo H. Interleukin-1 inhibits glucose-modulated insulin and glucagon secretion in rat islet monolayer cultures. Endocrinology. 1988 Jun;122(6):2393–2398. doi: 10.1210/endo-122-6-2393. [DOI] [PubMed] [Google Scholar]
  21. Sandler S., Andersson A., Hellerström C. Inhibitory effects of interleukin 1 on insulin secretion, insulin biosynthesis, and oxidative metabolism of isolated rat pancreatic islets. Endocrinology. 1987 Oct;121(4):1424–1431. doi: 10.1210/endo-121-4-1424. [DOI] [PubMed] [Google Scholar]
  22. Spinas G. A., Hansen B. S., Linde S., Kastern W., Mølvig J., Mandrup-Poulsen T., Dinarello C. A., Nielsen J. H., Nerup J. Interleukin 1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans. Diabetologia. 1987 Jul;30(7):474–480. doi: 10.1007/BF00279615. [DOI] [PubMed] [Google Scholar]
  23. Wang J. L., McDaniel M. L. Secretagogue-induced oscillations of cytoplasmic Ca2+ in single beta and alpha-cells obtained from pancreatic islets by fluorescence-activated cell sorting. Biochem Biophys Res Commun. 1990 Jan 30;166(2):813–818. doi: 10.1016/0006-291x(90)90882-n. [DOI] [PubMed] [Google Scholar]
  24. Wolf B. A., Hughes J. H., Florholmen J., Turk J., McDaniel M. L. Interleukin-1 inhibits glucose-induced Ca2+ uptake by islets of Langerhans. FEBS Lett. 1989 May 8;248(1-2):35–38. doi: 10.1016/0014-5793(89)80426-0. [DOI] [PubMed] [Google Scholar]
  25. Zawalich W. S., Diaz V. A. Interleukin 1 inhibits insulin secretion from isolated perifused rat islets. Diabetes. 1986 Oct;35(10):1119–1123. doi: 10.2337/diab.35.10.1119. [DOI] [PubMed] [Google Scholar]
  26. Zawalich W. S., Dierolf B., Zawalich K. C. Interleukin-1 induces time-dependent potentiation in isolated rat islets: possible involvement of phosphoinositide hydrolysis. Endocrinology. 1989 Feb;124(2):720–726. doi: 10.1210/endo-124-2-720. [DOI] [PubMed] [Google Scholar]

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