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. 1997 Feb 1;99(3):469–474. doi: 10.1172/JCI119181

Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2.

H Rothe 1, N A Jenkins 1, N G Copeland 1, H Kolb 1
PMCID: PMC507820  PMID: 9022080

Abstract

Recently, interferon-gamma-inducing-factor (IGIF) has been described as a novel monokine that is a more potent interferon-gamma (IFN-gamma) inducer than IL-12. By cloning IGIF from affected tissue and studying IGIF gene expression, we describe for the first time a close association of this cytokine with an autoimmune disease. The non-obese diabetic (NOD) mouse spontaneously develops autoimmune insulitis and diabetes which can be accelerated and synchronized by a single injection of cyclophosphamide. IGIF mRNA was demonstrated by reverse transcriptase PCR in NOD mouse pancreas during early stages of insulitis. Levels of IGIF mRNA increased rapidly after cyclophosphamide treatment and preceded a rise in IFN-gamma mRNA, and subsequently diabetes. Interestingly, these kinetics mimick that of IL-12p40 mRNA, resulting in a close correlation of individual mRNA levels. Cloning of the IGIF cDNA from pancreas RNA followed by sequencing revealed identity with the IGIF sequence cloned from Kupffer cells and in vivo preactivated macrophages. When extending our study to macrophages of the spleen we observed that NOD mouse macrophages responded to cyclophosphamide with IGIF gene expression while macrophages from Balb/c mice treated in parallel did not. The IGIF gene position is located within the Idd2 interval on mouse chromosome 9 and therefore it is a candidate for the Idd2 susceptible gene. We conclude that IGIF expression is abnormally regulated in autoimmune NOD mice and closely associated with diabetes development.

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Selected References

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  1. Bowman M. A., Leiter E. H., Atkinson M. A. Prevention of diabetes in the NOD mouse: implications for therapeutic intervention in human disease. Immunol Today. 1994 Mar;15(3):115–120. doi: 10.1016/0167-5699(94)90154-6. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Copeland N. G., Jenkins N. A. Development and applications of a molecular genetic linkage map of the mouse genome. Trends Genet. 1991 Apr;7(4):113–118. doi: 10.1016/0168-9525(91)90455-y. [DOI] [PubMed] [Google Scholar]
  4. Debray-Sachs M., Carnaud C., Boitard C., Cohen H., Gresser I., Bedossa P., Bach J. F. Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma. J Autoimmun. 1991 Apr;4(2):237–248. doi: 10.1016/0896-8411(91)90021-4. [DOI] [PubMed] [Google Scholar]
  5. Imai K., Kingsley D. M. Mouse chromosome 9. Mamm Genome. 1994;5(Spec No):S139–S153. [PubMed] [Google Scholar]
  6. Jenkins N. A., Copeland N. G., Taylor B. A., Lee B. K. Organization, distribution, and stability of endogenous ecotropic murine leukemia virus DNA sequences in chromosomes of Mus musculus. J Virol. 1982 Jul;43(1):26–36. doi: 10.1128/jvi.43.1.26-36.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Katz J. D., Benoist C., Mathis D. T helper cell subsets in insulin-dependent diabetes. Science. 1995 May 26;268(5214):1185–1188. doi: 10.1126/science.7761837. [DOI] [PubMed] [Google Scholar]
  8. Kolb-Bachofen V., Kolb H. A role for macrophages in the pathogenesis of type 1 diabetes. Autoimmunity. 1989;3(2):145–154. doi: 10.3109/08916938909019963. [DOI] [PubMed] [Google Scholar]
  9. McAleer M. A., Reifsnyder P., Palmer S. M., Prochazka M., Love J. M., Copeman J. B., Powell E. E., Rodrigues N. R., Prins J. B., Serreze D. V. Crosses of NOD mice with the related NON strain. A polygenic model for IDDM. Diabetes. 1995 Oct;44(10):1186–1195. doi: 10.2337/diab.44.10.1186. [DOI] [PubMed] [Google Scholar]
  10. Okamura H., Tsutsi H., Komatsu T., Yutsudo M., Hakura A., Tanimoto T., Torigoe K., Okura T., Nukada Y., Hattori K. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 1995 Nov 2;378(6552):88–91. doi: 10.1038/378088a0. [DOI] [PubMed] [Google Scholar]
  11. Pecker I., Avraham K. B., Gilbert D. J., Savitsky K., Rotman G., Harnik R., Fukao T., Schröck E., Hirotsune S., Tagle D. A. Identification and chromosomal localization of Atm, the mouse homolog of the ataxia-telangiectasia gene. Genomics. 1996 Jul 1;35(1):39–45. doi: 10.1006/geno.1996.0320. [DOI] [PubMed] [Google Scholar]
  12. Prochazka M., Leiter E. H., Serreze D. V., Coleman D. L. Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science. 1987 Jul 17;237(4812):286–289. doi: 10.1126/science.2885918. [DOI] [PubMed] [Google Scholar]
  13. Rothe H., Burkart V., Faust A., Kolb H. Interleukin-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice. Diabetologia. 1996 Jan;39(1):119–122. doi: 10.1007/BF00400422. [DOI] [PubMed] [Google Scholar]
  14. Rothe H., Faust A., Schade U., Kleemann R., Bosse G., Hibino T., Martin S., Kolb H. Cyclophosphamide treatment of female non-obese diabetic mice causes enhanced expression of inducible nitric oxide synthase and interferon-gamma, but not of interleukin-4. Diabetologia. 1994 Nov;37(11):1154–1158. doi: 10.1007/BF00418380. [DOI] [PubMed] [Google Scholar]
  15. Serreze D. V. Autoimmune diabetes results from genetic defects manifest by antigen presenting cells. FASEB J. 1993 Aug;7(11):1092–1096. doi: 10.1096/fasebj.7.11.8370480. [DOI] [PubMed] [Google Scholar]
  16. Shehadeh N. N., LaRosa F., Lafferty K. J. Altered cytokine activity in adjuvant inhibition of autoimmune diabetes. J Autoimmun. 1993 Jun;6(3):291–300. doi: 10.1006/jaut.1993.1025. [DOI] [PubMed] [Google Scholar]
  17. Signore A., Procaccini E., Toscano A. M., Ferretti E., Williams A. J., Beales P. E., Cugini P., Pozzilli P. Histological study of pancreatic beta-cell loss in relation to the insulitis process in the non-obese diabetic mouse. Histochemistry. 1994 Apr;101(4):263–269. doi: 10.1007/BF00315913. [DOI] [PubMed] [Google Scholar]
  18. Trembleau S., Penna G., Bosi E., Mortara A., Gately M. K., Adorini L. Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med. 1995 Feb 1;181(2):817–821. doi: 10.1084/jem.181.2.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994 Dec 15;84(12):4008–4027. [PubMed] [Google Scholar]

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