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Horm Metab Res 2002; 34(1): 7-12
DOI: 10.1055/s-2002-19959
Original Basic

© Georg Thieme Verlag Stuttgart · New York

Immunoregulation During Disease Progression in Prediabetic NOD Mice: Inverse Expression of Arginase and Prostaglandin H Synthase 2 vs. Interleukin-15

H.  Rothe 1, 2 , A.  Hausmann 1 , H.  Kolb 1
  • 1Germany Diabetes Research Institute at the Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
  • 2Institute of Diabetes Research, Munich, Germany
Further Information

Publication History

Received 3 July 2001

Accepted after Revision 19 September 2001

Publication Date:
14 August 2002 (online)

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Abstract

Non-obese diabetic (NOD) mice spontaneously develop insulin dependent diabetes due to autoimmune destruction of β-cells. The progression of insulitis can be accelerated and synchronized in the pancreas by a single injection of 250 mg/kg cyclophosphamide. In this study, we will report on three immune mediators that were not known to be expressed during insulitis until now. Early insulitis in ten-week-old female NOD mice was associated with strong expression of prostaglandin H synthase 2 in the pancreas and of arginase, an antagonist enzyme of the inducible NO synthase. After acceleration of insulitis progression by cyclophosphamide, expression of the two enzymes was downregulated within 24 h. There was strong concomitant upregulation of IL-15 gene expression that preceded lymphocyte invasion of islets and a rise of IFN-γ mRNA levels by several days. The comparison of individual pancreata showed that the expression of IL-12 and IL-18 mRNA closely correlated with levels of IL-15 gene expression. We conclude that arginase and prostaglandin H synthase 2 expression is associated with peri-insulitis, while IL-15 is a candidate cytokine in driving destructive insulitis, as it elicits Th1-cytotoxic responses in lymphoid as well as in non-lymphoid immune cells and is unusually resistant to downregulation by antagonistic cytokines. This is the first report on arginase, prostaglandin H synthase 2 and IL-15 expression in pancreatic lesions of prediabetic NOD mice.

Key words

Non-Obese Diabetic Mice - Insulitis - Cytokines - Innate Immunity - Macrophages - Cyclophosphamide

References

  • 1 Hanenberg H, Kolb-Bachofen V, Kantwerk-Funke G, Kolb H. Macrophage infiltration precedes and is prerequisite for lymphocytic insulitis in pancreatic islets of prediabetic BB rats.  Diabetologia. 1989;  32 126-129
    CrossrefPubMedGoogle Scholar
  • 2 Lee K U, Amano K, Yoon J W. Evidence for initial involvement of macrophages in development of insulitis in NOD mice.  Diabetes. 1989;  37 989-991
    PubMedGoogle Scholar
  • 3 Oschilewski U, Kiesel U, Kolb H. Administration of silica prevents diabetes in BB rats.  Diabetes. 1985;  34 197-202
    PubMedGoogle Scholar
  • 4 Rothe H, Fehsel K, Kolb H. A macrophage defect in diabetes prone BB rats.  Diabetologia. 1990;  33 573-575
    CrossrefPubMedGoogle Scholar
  • 5 Serreze D V, Gaedeke J W, Leiter E H. Hematopoietic stem-cell defects underlying abnormal macrophage development and maturation in NOD/Lt mice: defective regulation of cytokine receptors and protein kinase C.  Proc Natl Acad Sci USA. 1993;  90 9625-9629
    PubMedGoogle Scholar
  • 6 Jansen A, van Hagen M, Drexhage H A. Defective maturation and function of antigen-presenting cells in type I diabetes.  Lancet. 1990;  345 491-492
    PubMedGoogle Scholar
  • 7 Tafuri A, Bowers W E, Handler E S, Appel M, Lew R, Greiner D, Mordes J P, Rossini A A. High stimulatory activity of dendritic cells from diabetes-prone BioBreeding/Worcester rats exposed to macrophage-derived factors.  J Clin Invest. 1993;  91 2040-2048
    PubMedGoogle Scholar
  • 8 Baxter A G, Kinder S J, Hammond K J, Scollay R, Godfrey D I. Association between alphabetaTCR+CD4-CD8- T-cell deficiency and IDDM in NOD/Lt mice.  Diabetes. 1997;  46 572-582
    PubMedGoogle Scholar
  • 9 Wilson S B, Kent S C, Patton K T, Orbanm T, Jackson R A, Exley M, Porcelli S, Schatz D A, Atkinson M A, Balk S P, Strominger J L, Hafler D L. Extreme Th1 bias of invariant Valpha24JalphaQ T cells in type I diabetes.  Nature. 1998;  391 177-181
    CrossrefPubMedGoogle Scholar
  • 10 Medzhitov R, Janeway J r. Innate immunity: The virtues of a nonclonal system of recognition.  Cell. 1997;  91 295-298
    CrossrefPubMedGoogle Scholar
  • 11 Germann T, Partenheimer A, Rüde E. Requirements for the growth of Th1 lymphocyte clones.  Eur J Immunol. 1990;  20 2035-2040
    PubMedGoogle Scholar
  • 12 Weaver C T, Unanue E R. The costimulatory function of antigen presenting cells.  Immunol Today. 1990;  11 49-55
    CrossrefPubMedGoogle Scholar
  • 13 Signore A, Procaccini E, Toscano A M, Ferretti E, Williams E 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;  101 263-269
    CrossrefPubMedGoogle Scholar
  • 14 Kolb H. Benign versus destructive insulitis.  Diabetes/Metab Rev. 1997;  13 139-146
    PubMedGoogle Scholar
  • 15 Harda M, Makino S. Promotion of spontaneous diabetes in non-obese diabetes-prone mice by cyclophosphamide.  Diabetologia. 1984;  27 604-606
    CrossrefPubMedGoogle Scholar
  • 16 Yasunami R, Bach J F. Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice.  Eur J Immunol. 1988;  18 481-484
    PubMedGoogle Scholar
  • 17 Rabinovitch A. An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus.  Diabetes Metab Rev. 1998;  14 129-151
    PubMedGoogle Scholar
  • 18 Rothe H, Faust H, 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;  37 1154-1158
    PubMedGoogle Scholar
  • 19 Grabstein K H, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn M A, Ahdieh M. et al . Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor.  Science. 1994;  264 965-968
    PubMedGoogle Scholar
  • 20 Carson W E, Ross M E, Baicchi R A, Marien M J, Boiani N, Grabstein K, Caligiuri M A. Endogenous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro.  J Clin Invest. 1995;  96 2578-2582
    PubMedGoogle Scholar
  • 21 Doherty T M, Seder R A, Sher A. Induction and regulation of IL-15 expression in murine macrophages.  J Immunol. 1996;  156 735-741
    PubMedGoogle Scholar
  • 22 Waldmann T, Tagaya Y. The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens.  Annu Rev Immunol. 1999;  17 19-49
    CrossrefPubMedGoogle Scholar
  • 23 Ruchatz H, Leung B P, Wie X Q, McInnes I B, Liew F Y. Soluble IL-15 receptor alpha-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology.  J Immunol. 1980;  160 5654-5660
    PubMedGoogle Scholar
  • 24 Thurkow E W, van der Heijden I M, Breedveld F C, Smeets T J, Daha M R, Kluin P M, Meinders A E, Tak P P. Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared with patients with Yersinia-induced arthritis and osteoarthritis.  J Pathol. 1997;  181 444-450
    PubMedGoogle Scholar
  • 25 Fehniger T A, Caligiuri M A. Interleukin 15: biology and relevance to human disease.  Blood. 2001;  97 14-32
    CrossrefPubMedGoogle Scholar
  • 26 Maiuri L, Ciacci C, Auricchio S, Brown V, Quarantino S, Londei M. Interleukin 15 mediates epithelial changes in celiac disease.  Gastroenterology. 2000;  119 996-1006
    PubMedGoogle Scholar
  • 27 Kuroda E, Sugiura T, Zeki K, Yoshida Y, Yamashita U. Sensitivity difference to the suppressive effect of prostaglandin E2 among mouse strains: a possible mechanism to polarize Th2 type response in BALB/c mice.  J Immunol. 2000;  164 2386-2395
    PubMedGoogle Scholar
  • 28 Munder M, Eichmann K, Modolell M. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype.  J Immunol. 1998;  160 5347-5354
    PubMedGoogle Scholar
  • 29 Rothe H, O'Hara R, Martin S, Kolb H. Suppression of diabetes development in the cyclophosphamide induced diabetes of the NOD mice by treatment with IL-12p40 homodimer.  Diabetologia. 1997;  40 641-646
    CrossrefPubMedGoogle Scholar
  • 30 Rothe H, Jenkins N A, Copeland N G, Kolb H. Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2.  J Clin Invest. 1997;  99 469-474
    PubMedGoogle Scholar
  • 31 Campell 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;  97 739-742
    PubMedGoogle Scholar
  • 32 Ylinen L, Teros T, Liukas A, Arvilommi P, Sainio-Pollanen S, Verajankorva E, Pollanen P, Simell O. The role of lipid antigen presentation, cytokine balance, and major histocompatibility complex in a novel murine model of adoptive transfer of insulitis.  Pancreas. 2000;  20 197-205
    PubMedGoogle Scholar
  • 33 Reddy S, Yip S, Karanam M, Poole C A, Ross J M. An immunohistochemical study of macrophage influx and the co-localization of inducible nitric oxide synthase in the pancreas of non-obese diabetic (NOD) mice during disease acceleration with cyclophosphamide.  Histochem J. 1999;  31 303-304
    PubMedGoogle Scholar
  • 34 Fantuzzi G, Reed D A, Dinarello C A. IL-12-induced IFN-γ is dependent on caspase-1 processing of the IL-18 precursor.  J Clin Invest. 1999;  104 761-767
    PubMedGoogle Scholar
  • 35 Vazquez N, Walsh T J, Friedman D, Chanock S J, Lyman C A. Interleukin-15 augments superoxide production and microbicidal activity of human monocytes against Candida albicans.  Infection Immun. 1998;  66 145-150
    PubMedGoogle Scholar
  • 36 Marks-Konczalik J, Dubois S, Losi J M, Sabzevari H, Yamada N, Feigenbaum L, Waldmann T A, Tagaya Y. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice.  Proc Natl Acad Sci USA. 2000;  97 11 445-11 450
    PubMedGoogle Scholar
  • 37 Waldmann T A, Dubois S, Tagaya Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy.  Immunity. 2001;  14 105-110
    PubMedGoogle Scholar
  • 38 Trembleau S, Penna G, Gregori S, Chapman H D, Serreze D V, Magram J, Adorini L. Pancreas-infiltrating Th1 cells and diabetes develop in IL-12 deficient nonobese diabetic mice.  J Immunol. 1999;  163 2960-2968
    PubMedGoogle Scholar
  • 39 Hill J R, Corbett J A, Baldwin A C, McDaniel M L. Nitric oxide production by the rat insulinoma cell line, RINm5F, is specific for IL-1: a spectrophotometric IL-1 bioassay.  Anal Biochem. 1996;  236 14-19
    CrossrefPubMedGoogle Scholar
  • 40 Benhamou P Y, Mullen Y, Clare-Salzler M, Sangkharat A, Benhamou C, Shevlin L, Go V L. Essential fatty acid deficiency prevents autoimmune diabetes in nonobese diabetic mice throuh a positive impact on antigen-presenting cells and Th2 lymphocytes.  Pancreas. 1995;  11 26-37
    PubMedGoogle Scholar
  • 41 Gilroy D W, Colville-Nash P R, Willis D, Chivers J, Paul-Clark M J, Willoughby D A. Inducible cyclooxygenase may have anti-inflammatory properties.  Nature Med. 1999;  5 698-701
    PubMedGoogle Scholar
  • 42 Demeure C E, Yang L P, Desjardins C, Raynauld P, Delespesse G. Prostaglandin E2 primes naive T cells for the production of anti-inflammatory cytokines.  Eur J Immunol. 1997;  27 3526-3531
    PubMedGoogle Scholar
  • 43 Hancock W W, Polanski M, Zhang J, Blogg N, Weiner H L. Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E.  Am J Pathol. 1995;  147 1193-1198
    PubMedGoogle Scholar
  • 44 Joshi P D, Zhou X, Cuchens M, Jones Q. Prostaglandin E2 suppressed IL-15-mediated human NK cell function through down-regulation of common gamma-chain.  J Immunol. 2001;  166 885-891
    PubMedGoogle Scholar

Prof. Dr. H. Kolb

German Diabetes Research Institute

Auf'm Hennekamp 65 · 40225 Düsseldorf · Germany

Phone: + 49 (211) 3382 643

Fax: + 49 (211) 3382 606

Email: kolb@ddfi.uni-duesseldorf.de