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

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. ResultsReg2 was upregulated in islets from the NOD RIPHuIFNβ 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.

Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren's syndrome

“…These results support the idea that REG Iα mRNA over-expression is associated with inflammation triggered by autoimmune disorders such as SS. It was reported that Reg gene expression was regulated by several factors, such as nicotinamide [18,19], glucocorticoids [18,20], nutrient factors [21], IL-6 [12,18], IL-8 [22], IL-11 [23], IL-22 [24], IFN-γ [25], IFN-β [12] and CINC-2β [26]. Among the major inflammatory mediators involved in the induction of inflammation of the salivary glands with primary SS, IL-6 is an important proinflammatory cytokine in relation to lymphocyte infiltration [27,28].…”

“…IL-6 and IL-8 are reported to induce REG Iα mRNA in vitro [18,21,22] and in vivo [39], and IL-11 [23], IL-22 [24], IFN-γ [25], IFN-β [12] and CINC-2β [26] are also reported to induce REG Iα mRNA. IL-6R and gp130 are known as signal transducers of IL-6.…”

“…Types I and II Reg proteins are expressed in regenerating islets [4,11,12]. Type III Reg proteins have been suggested to be involved in cellular proliferation in intestinal cells, hepatic cells and neuronal cells.…”

“…It has been reported that the expression of Reg family genes was regulated by several factors such as nicotinamide [18,19], glucocorticoids [18,20], nutrient factors [21], interleukin (IL)-6 [12,18], IL-8 [22], IL-11 [23], IL-22 [24] interferon (IFN)-γ [25], IFN-β [12] and cytokine-induced neutrophil chemoattractant-2 (CINC-2)β [26]. We examined the mRNA levels of IL-6 and IL-8, major proinflammatory cytokines produced in MSG in SS patients [27][28][29][30], in MSG specimens.…”

Adjuvant Immunotherapy Increases β Cell Regenerative Factor Reg2 in the Pancreas of Diabetic Mice

“…The specificity of the overexpression of Reg2 in the diabetogenic process was reinforced by the fact that it was also observed in NOD male mice after treatment with cyclophosphamide, whereas this drug has no effect in male control mice. Other stimuli for Reg2 expression related to T1D are diet (18), type 1 IFN (19), and insulin-like growth factor-1 (20) among others.…”