Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1994 Jul;145(1):157–166.

Islet inflammation and hyperplasia induced by the pancreatic islet-specific overexpression of interleukin-6 in transgenic mice.

I L Campbell 1, M V Hobbs 1, J Dockter 1, M B Oldstone 1, J Allison 1
PMCID: PMC1887304  PMID: 8030746

Abstract

Interleukin-6 (IL-6) is thought to be involved in the pathogenesis of autoimmune insulin-dependent diabetes mellitus. To examine this possibility, we developed two lines of transgenic mice (termed RIP-IL6) which overexpressed IL-6 in the pancreatic islet beta cells. RIP-IL6 mice, while showing a modest reduction in body weight, remained normoglycemic throughout their lives. Furthermore, insulin gene expression and glucose tolerance were similar to non-transgenic littermates. Histopathological examination revealed significant changes in the pancreas but not other organs of RIP-IL6 animals, with marked alterations in the architecture of the islets, in the islet cells, and in surrounding tissues. In younger animals these changes included islet hyperplasia with increased mitotic figures, neo-ductular formation, fibrosis, and a scant mononuclear cell infiltration (insulitis). In addition, immunostaining for islet hormones revealed changes in both the topography and density of beta and alpha cells. In older RIP-IL6 mice, a more florid insulitis was observed which was composed predominantly of B220+ B lymphocytes and, to a lesser extent, Mac-1+ macrophages and CD4+ and CD8+ T lymphocytes. Immunostaining for mouse IgG revealed significant numbers of plasma cells in the peri-islet infiltrates, which suggested that IL-6 induced differentiation of the recruited B lymphocytes. Therefore, islet overexpression of IL-6 produces a complex, localized host response implicating this cytokine in not only inflammatory processes that occur in autoimmune diabetes but also cellular neogenesis, which may indicate a role in tissue repair.

Full text

PDF
159

Images in this article

159Figure 1
on p.159
160Figure 2
on p.160
161Figure 3
on p.161
162Figure 4
on p.162
162Figure 5
on p.162
163Figure 6
on p.163
164Figure 7
on p.164

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akira S., Hirano T., Taga T., Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 1990 Aug;4(11):2860–2867. [PubMed] [Google Scholar]
  2. Allison J., Campbell I. L., Morahan G., Mandel T. E., Harrison L. C., Miller J. F. Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic beta cells. Nature. 1988 Jun 9;333(6173):529–533. doi: 10.1038/333529a0. [DOI] [PubMed] [Google Scholar]
  3. Allison J., Malcolm L., Chosich N., Miller J. F. Inflammation but not autoimmunity occurs in transgenic mice expressing constitutive levels of interleukin-2 in islet beta cells. Eur J Immunol. 1992 May;22(5):1115–1121. doi: 10.1002/eji.1830220503. [DOI] [PubMed] [Google Scholar]
  4. Badley J. E., Bishop G. A., St John T., Frelinger J. A. A simple, rapid method for the purification of poly A+ RNA. Biotechniques. 1988 Feb;6(2):114–116. [PubMed] [Google Scholar]
  5. 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]
  6. Brandt S. J., Bodine D. M., Dunbar C. E., Nienhuis A. W. Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice. J Clin Invest. 1990 Aug;86(2):592–599. doi: 10.1172/JCI114749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Campbell I. L., Cutri A., Wilson A., Harrison L. C. Evidence for IL-6 production by and effects on the pancreatic beta-cell. J Immunol. 1989 Aug 15;143(4):1188–1191. [PubMed] [Google Scholar]
  8. Campbell I. L., Harrison L. C. Molecular pathology of type 1 diabetes. Mol Biol Med. 1990 Aug;7(4):299–309. [PubMed] [Google Scholar]
  9. Campbell I. L., Hobbs M. V., Kemper P., Oldstone M. B. Cerebral expression of multiple cytokine genes in mice with lymphocytic choriomeningitis. J Immunol. 1994 Jan 15;152(2):716–723. [PubMed] [Google Scholar]
  10. Campbell I. L., Iscaro A., Harrison L. C. IFN-gamma and tumor necrosis factor-alpha. Cytotoxicity to murine islets of Langerhans. J Immunol. 1988 Oct 1;141(7):2325–2329. [PubMed] [Google Scholar]
  11. Campbell I. L., Kay T. W., Oxbrow L., Harrison L. C. Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. J Clin Invest. 1991 Feb;87(2):739–742. doi: 10.1172/JCI115055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Campbell I. L., Oxbrow L., Harrison L. C. Reduction in insulitis following administration of IFN-gamma and TNF-alpha in the NOD mouse. J Autoimmun. 1991 Apr;4(2):249–262. doi: 10.1016/0896-8411(91)90022-5. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Chiu C. P., Moulds C., Coffman R. L., Rennick D., Lee F. Multiple biological activities are expressed by a mouse interleukin 6 cDNA clone isolated from bone marrow stromal cells. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7099–7103. doi: 10.1073/pnas.85.19.7099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Garman R. D., Jacobs K. A., Clark S. C., Raulet D. H. B-cell-stimulatory factor 2 (beta 2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7629–7633. doi: 10.1073/pnas.84.21.7629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gu D., Sarvetnick N. Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development. 1993 May;118(1):33–46. doi: 10.1242/dev.118.1.33. [DOI] [PubMed] [Google Scholar]
  17. Hanahan D. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature. 1985 May 9;315(6015):115–122. doi: 10.1038/315115a0. [DOI] [PubMed] [Google Scholar]
  18. Heinrich P. C., Castell J. V., Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990 Feb 1;265(3):621–636. doi: 10.1042/bj2650621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Helle M., Brakenhoff J. P., De Groot E. R., Aarden L. A. Interleukin 6 is involved in interleukin 1-induced activities. Eur J Immunol. 1988 Jun;18(6):957–959. doi: 10.1002/eji.1830180619. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Hirano T., Akira S., Taga T., Kishimoto T. Biological and clinical aspects of interleukin 6. Immunol Today. 1990 Dec;11(12):443–449. doi: 10.1016/0167-5699(90)90173-7. [DOI] [PubMed] [Google Scholar]
  22. Hirano T., Matsuda T., Turner M., Miyasaka N., Buchan G., Tang B., Sato K., Shimizu M., Maini R., Feldmann M. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988 Nov;18(11):1797–1801. doi: 10.1002/eji.1830181122. [DOI] [PubMed] [Google Scholar]
  23. Hobbs M. V., Weigle W. O., Noonan D. J., Torbett B. E., McEvilly R. J., Koch R. J., Cardenas G. J., Ernst D. N. Patterns of cytokine gene expression by CD4+ T cells from young and old mice. J Immunol. 1993 Apr 15;150(8 Pt 1):3602–3614. [PubMed] [Google Scholar]
  24. Le J. M., Vilcek J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest. 1989 Dec;61(6):588–602. [PubMed] [Google Scholar]
  25. Meda P., Hooghe-Peters E. L., Orci L. Monolayer cultures of adult pancreatic islet cells on osmotically disrupted fibroblasts. Diabetes. 1980 Jun;29(6):497–500. doi: 10.2337/diab.29.6.497. [DOI] [PubMed] [Google Scholar]
  26. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  27. Nakajima K., Martínez-Maza O., Hirano T., Breen E. C., Nishanian P. G., Salazar-Gonzalez J. F., Fahey J. L., Kishimoto T. Induction of IL-6 (B cell stimulatory factor-2/IFN-beta 2) production by HIV. J Immunol. 1989 Jan 15;142(2):531–536. [PubMed] [Google Scholar]
  28. Picarella D. E., Kratz A., Li C. B., Ruddle N. H., Flavell R. A. Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. J Immunol. 1993 May 1;150(9):4136–4150. [PubMed] [Google Scholar]
  29. 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]
  30. Rabinovitch A., Russell T., Mintz D. H. Factors from fibroblasts promote pancreatic islet B cell survival in tissue culture. Diabetes. 1979 Dec;28(12):1108–1113. doi: 10.2337/diab.28.12.1108. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Sarvetnick N., Shizuru J., Liggitt D., Martin L., McIntyre B., Gregory A., Parslow T., Stewart T. Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature. 1990 Aug 30;346(6287):844–847. doi: 10.1038/346844a0. [DOI] [PubMed] [Google Scholar]
  33. Steiner H., Oelz O., Zahnd G., Foresch E. R. Studies on islet cell regeneration, hyperplasia and intrainsular cellular interrelations in long lasting streptozotocin diabetes in rats. Diabetologia. 1970 Dec;6(6):558–564. doi: 10.1007/BF00418221. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Suematsu S., Matsuda T., Aozasa K., Akira S., Nakano N., Ohno S., Miyazaki J., Yamamura K., Hirano T., Kishimoto T. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7547–7551. doi: 10.1073/pnas.86.19.7547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tokunaga K., Taniguchi H., Yoda K., Shimizu M., Sakiyama S. Nucleotide sequence of a full-length cDNA for mouse cytoskeletal beta-actin mRNA. Nucleic Acids Res. 1986 Mar 25;14(6):2829–2829. doi: 10.1093/nar/14.6.2829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ullrich A., Shine J., Chirgwin J., Pictet R., Tischer E., Rutter W. J., Goodman H. M. Rat insulin genes: construction of plasmids containing the coding sequences. Science. 1977 Jun 17;196(4296):1313–1319. doi: 10.1126/science.325648. [DOI] [PubMed] [Google Scholar]
  38. Van Snick J., Cayphas S., Szikora J. P., Renauld J. C., Van Roost E., Boon T., Simpson R. J. cDNA cloning of murine interleukin-HP1: homology with human interleukin 6. Eur J Immunol. 1988 Feb;18(2):193–197. doi: 10.1002/eji.1830180202. [DOI] [PubMed] [Google Scholar]
  39. Wogensen L., Huang X., Sarvetnick N. Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans. J Exp Med. 1993 Jul 1;178(1):175–185. doi: 10.1084/jem.178.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Woodroofe M. N., Sarna G. S., Wadhwa M., Hayes G. M., Loughlin A. J., Tinker A., Cuzner M. L. Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol. 1991 Sep;33(3):227–236. doi: 10.1016/0165-5728(91)90110-s. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES