nach oben

Erschienen in:

01.10.2006 | Article

Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNβ

verfasst von: R. Planas, A. Alba, J. Carrillo, M. C. Puertas, R. Ampudia, X. Pastor, H. Okamoto, S. Takasawa, W. Gurr, R. Pujol-Borrell, J. Verdaguer, M. Vives-Pi

Erschienen in: Diabetologia | Ausgabe 10/2006

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

The expression of IFNβ in beta cells results in accelerated type 1 diabetes. The REG family of beta cell proliferation factors have been described as autoantigens in autoimmune diabetes. The aim of this study was to determine the effect of IFNβ on Reg expression, and the implications of this in terms of autoimmunity.

Methods

Reg gene expression was determined in islets from non-obese diabetic (NOD) RIP-HuIFNβ mice by cDNA microarray, quantitative real-time PCR and immunohistochemistry. The effect of IFNβ on Reg1 and Reg2 expression was assessed in the NOD insulinoma cell line NIT-1. IL-6, known to induce Reg expression, was measured in the insulitis microenvironment. Morphological studies were carried out to determine islet enlargement in this model.

Results

Reg2 was upregulated in islets from the NOD RIP-HuIFNβ mice at the onset of the autoimmune attack. IFNβ upregulates Reg1 and Reg2 genes in NIT-1 cells. The expression of Il6 was increased in islets from transgenic mice and in NIT-1 cells exposed to HuIFNβ. Moreover, islets from transgenic mice were enlarged compared with those from wild-type mice.

Conclusions/interpretation

Reg overexpression correlates well with the acceleration of diabetes in this model. The upregulation of Reg suggests that islets try to improve hyperglycaemia by regenerating the cells lost in the autoimmune attack. Reg expression is regulated by several factors such as inflammation. Therefore, the overexpression of an IFNβ-induced autoantigen (REG) in the islets during inflammation might contribute to the premature onset of diabetes.

Bach JF, Chatenoud L (2001) Tolerance to islet autoantigens in type I diabetes. Annu Rev Immunol 19:131–161PubMedCrossRef

Jun HS, Yoon JW (2003) A new look at viruses in type 1 diabetes. Diabetes Metab Res Rev 19:8–31PubMedCrossRef

Maugh TH (1975) Diabetes: epidemiology suggests a viral connection. Science 188:347–351CrossRefPubMed

Banatvala JE, Bryant J, Schernthaner G et al (1985) Coxsackie B, mumps, rubella and cytomegalovirus specific IgM responses in patients with insulin-dependent diabetes mellitus in Britain, Austria and Australia. Lancet 1:1409–1412PubMedCrossRef

Foulis AK, Farquharson MA, Meager A (1987) Immunoreactive alpha interferon in insulin secreting beta cells in type 1 diabetes mellitus. Lancet 2:1423–1427PubMedCrossRef

Somoza N, Vargas F, Roura-Mir C et al (1994) Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile. J Immunol 153:1360–1377PubMed

Huang X, Yuang J, Goddard A et al (1995) Interferon expression in the pancreases of patients with type I diabetes. Diabetes 44:658–664PubMedCrossRef

Alba A, Puertas MC, Carrillo J et al (2004) IFNbeta accelerates autoimmune type diabetes in nonobese diabetic mice and breaks the tolerance to beta cells in non-diabetes-prone mice. J Immunology 173:6667–6675

Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447–485PubMedCrossRef

10.

Gurr W, Yavari R, Wen L et al (2002) A Reg family protein is overexpressed in islets from a patient with new-onset type 1 diabetes and acts as T cell autoantigen in NOD mice. Diabetes 51:339–346PubMedCrossRef

11.

Shervani NJ, Takasawa S, Uchigata Y et al (2004) Autoantibodies to REG, a beta-cell regeneration factor, in diabetic patients. Eur J Clin Invest 34:752–758PubMedCrossRef

12.

Terazono K, Yamamoto H, Takasawa S et al (1988) A novel gene activated in regenerating islets. J Biol Chem 263:2111–2114PubMed

13.

Zhang YW, Ding LS, Lai MD (2003) Reg gene family and human diseases. World J Gastroenterol 9:2635–2641PubMed

14.

Sekikawa A, Fukui H, Fujii S et al (2005) Possible role of REG I alpha protein in ulcerative colitis and colitic cancer. Gut 54:1437–1444PubMedCrossRef

15.

Ogawa H, Fukushima K, Naito H et al (2003) Increased expression of HIP/PAP and regenerating gene III in human inflammatory bowel disease and a murine bacterial reconstitution model. Inflamm Bowel Dis 9:162–170PubMedCrossRef

16.

Terazono K, Uchiyama Y, Ide M et al (1990) Expression of Reg protein in rat regenerating islets and its co-localisation with insulin in the beta cell secretory granules. Diabetologia 33:250–252PubMedCrossRef

17.

Okamoto H (1999) The Reg gene family and Reg proteins: with special attention to the regeneration of pancreatic beta cells. J Hepatobiliary Pancreat Surg 6:254–262PubMedCrossRef

18.

Watanabe T, Yonemura Y, Yonekura H et al (1994) Pancreatic beta cell replication and amelioration of surgical diabetes by Reg protein. Proc Natl Acad Sci USA 91:3589–3592PubMedCrossRef

19.

Unno M, Nata K, Noguchi N et al (2002) Production and characterisation of Reg knockout mice. Diabetes 51(Suppl 3):S478–S483PubMedCrossRef

20.

Gross DJ, Weiss L, Reibstein I et al (1998) Amelioration of diabetes in nonobese diabetic mice with advanced disease by linomide induced immunoregulation combined with Reg protein treatment. Endocrinology 139:2369–2374PubMedCrossRef

21.

Qiu L, List EO, Kopchick JJ (2005) Differentially expressed proteins in the pancreas of diet induced diabetic mice. Mol Cell Proteomics 4:1311–1318PubMedCrossRef

22.

Yoshino N, Ishihara S, Rumi MA et al (2005) Interleukin-8 regulates expression of Reg protein in Helicobacter pylori-infected gastric mucosa. Am J Gastroenterol 100:2157–2166PubMedCrossRef

23.

Hamaguchi K, Gaskins HR, Leiter EH (1991) NIT-1, a pancreatic β-cell line established from a transgenic NOD/Lt mouse. Diabetes 40:842–849PubMedCrossRef

24.

Dhib-Jalbut SS, Cowan EP (1993) Direct evidence that interferon-beta mediates enhanced HLA-class I expression in measles virus-infected cells. J Immunol 151:6248–6258PubMed

25.

Pelegrin M, Devedjian DJ, Costa C et al (1998) Evidence from transgenic mice that interferon-beta may be involved in the onset of diabetes mellitus. J Biol Chem 20:12332–12340CrossRef

26.

Prochazka M, Gaskins HR, Shultz LD, Leiter EH (1992) The nonobese diabetic SCID mouse: model for spontaneous thymomagenesis associated immunodeficiency. Proc Natl Acad Sci USA 89:3290–3294PubMedCrossRef

27.

Serreze DV, Fleming SA, Chapman HD, Richard SD, Leiter EH, Tisch RM (1998) B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in non obese diabetic mice. J Immunol 161:3912–3918PubMed

28.

Vargas F, García-Cuyás F, Julián JF et al (2001) Engraftment of islets obtained by collagenase and liberase in diabetic rats: a comparative study. Pancreas 23:406–413PubMedCrossRef

29.

Vives-Pi M, Somoza N, Vargas F et al (1993) Expression of glutamic acid decarboxylase (GAD) in the alpha, beta and delta cells of normal and diabetic pancreas: implications for the pathogenesis of type 1 diabetes. Clin Exp Immunol 92:391–396PubMedCrossRef

30.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression using real-time quantitative PCR and the 2^−ΔΔCt method. Methods 25:402–408PubMedCrossRef

31.

Yonemura Y, Takashima T, Miwa K, Miyazaki I, Yamamoto H, Okamoto H (1984) Amelioration of diabetes mellitus in partially depancreatised rats by poly (ADP-ribose) synthetase inhibitors: evidence of islet beta-cell regeneration. Diabetes 33:401–404PubMedCrossRef

32.

Montanya E, Nacher V, Biarnes M, Soler J (2000) Linear correlation between beta cell mass and body weight throughout the lifespan in Lewis rats. Diabetes 49:1341–1346PubMedCrossRef

33.

Brod SA, Marshall GD Jr, Henninger EM, Sriram S, Khan M, Wolinsky JS (1996) Interferon-beta 1b treatment decreases tumor necrosis factor-alpha and increases interleukin-6 production in multiple sclerosis. Neurology 46:1633–1638PubMed

34.

Theofilopoulos AN, Baccala R, Beutler B, Kono DH (2005) Type I interferons in immunity and autoimmunity. Annu Rev Immunol 23:307–335PubMedCrossRef

35.

Campbell IL, Hoobs MV, Dockter J et al (1994) Islet inflammation and hyperplasia induced by the pancreatic islet-specific overexpression of interleukin-6 in transgenic mice. Am J Pathol 145:157–166PubMed

36.

Der SD, Zhou A, Williams BRG, Silverman RH (1998) Identification of genes differentially regulated by interferon alpha, beta or gamma using oligonucleotide arrays. Proc Natl Acad Sci USA 95:15623–15628PubMedCrossRef

37.

Campbell IL, Curti A, Wilson A, Harrison LC (1989) Evidence for IL6: production by and effects on the pancreatic beta cells. J Immunol 143:1188–1191PubMed

38.

Filippi C, von Herrath M (2005) How viral infections affect the autoimmune process leading to type 1 diabetes. Cell Immunol 233:125–132PubMedCrossRef

39.

Serreze DW, Hamaguchi K, Leiter EH (1989) Immunostimulation circumvents diabetes in NOD/Lt mice. J Autoimmun 2:759–776PubMedCrossRef

40.

Sobel DO, Goyal D, Ahvazi B et al (1998) Low dose poly I:C prevents diabetes in the diabetes prone BB rat. J Autoimmun 11:343–352PubMedCrossRef

41.

Rosmalen JGM, Leenen PJM, Pelegri C, Drexhage HA, Homo-Delarche F (2000) Islet abnormalities associated with an early influx of dendritic cells and macrophages in NOD and NODscid mice. Lab Invest 80:769–777PubMedCrossRef

42.

Simons PJ, Delemarre FG, Drexhage HA (1998) Antigen presenting dendritic cells as regulators of the growth of thyrocytes: a role of interleukin-1 beta and interleukin-6. Endocrinology 139:3148–3156PubMedCrossRef

43.

Gu D, Sarvetnik N (1993) Epithelial cell proliferation and islet neogenesis in IFN-gamma transgenic mice. Development 118:33–46PubMed

44.

Matos M, Park, Mathis D, Benoist C (2004) Progression to islet destruction. Diabetes 53:2310–2321PubMedCrossRef

45.

Meier JJ, Bhushan A, Butler AE, Risza RA, Butler PC (2005) Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48:2221–2228PubMedCrossRef

Titel: Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNβ
verfasst von: R. Planas
A. Alba
J. Carrillo
M. C. Puertas
R. Ampudia
X. Pastor
H. Okamoto
S. Takasawa
W. Gurr
R. Pujol-Borrell
J. Verdaguer
M. Vives-Pi
Publikationsdatum: 01.10.2006
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 10/2006
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0365-6

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 10/2006

Circulating ghrelin concentrations are lowered by intracerebroventricular insulin

Type 2 diabetes and cardiovascular risk in the UK south Asian community

A perfusion protocol for highly efficient transduction of intact pancreatic islets of Langerhans

Differential effects of IRS1 phosphorylated on Ser307 or Ser632 in the induction of insulin resistance by oxidative stress

Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes