Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNbeta.
OBJECTIVE
The expression of IFNbeta 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 IFNbeta 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-HuIFNbeta mice by cDNA microarray, quantitative real-time PCR and immunohistochemistry. The effect of IFNbeta 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-HuIFNbeta mice at the onset of the autoimmune attack. IFNbeta 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 HuIFNbeta. Moreover, islets from transgenic mice were enlarged compared with those from wild-type mice.


CONCLUSIONS
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 IFNbeta-induced autoantigen (REG) in the islets during inflammation might contribute to the premature onset of diabetes.
Planas
R
R
Laboratory of Immunobiology for Research and Diagnostic Applications (LIRAD), Blood and Tissue Bank, Germans Trias i Pujol University Hospital, PO Box 72, 08916, Badalona, Barcelona, Spain.
Alba
A
A
Carrillo
J
J
Puertas
M C
MC
Ampudia
R
R
Pastor
X
X
Okamoto
H
H
Takasawa
S
S
Gurr
W
W
Pujol-Borrell
R
R
Verdaguer
J
J
Vives-Pi
M
M
D000818:Animals; D002460:Cell Line; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000235:genetics; D016899:Interferon-beta / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology / Q000503:physiopathology*; D051847:Lithostathine / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD / Q000276:immunology; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007328:Insulin; D051847:Lithostathine; C497617:REG1A protein, human; D016899:Interferon-beta