Abstract
Regenerating (REG) proteins are associated with islet development, β-cell damage, diabetes and pancreatitis. Particularly, REG-1 and REG-3-beta are involved in cell growth/survival and/or inflammation and the Reg1 promoter contains interleukin-6 (IL-6)-responsive elements. We showed by transcriptome analysis that islets of Goto-Kakizaki (GK) rats, a model of spontaneous type 2 diabetes, overexpress Reg1, 3α, 3β and 3γ, vs Wistar islets. Goto-Kakizaki rat islets also exhibit increased cytokine/chemokine expression/release, particularly IL-6. Here we analyzed Reg1 and Reg3β expression and REG-1 immuno-localization in the GK rat pancreas in relationship with inflammation. Isolated pancreatic islets and acinar tissue from male adult Wistar and diabetic GK rats were used for quantitative RT-PCR analysis. REG-1 immunohistochemistry was performed on paraffin sections with a monoclonal anti-rat REG-1 antibody. Islet cytokine/chemokine release was measured after 48 h-culture. Islet macrophage-positive area was quantified on cryostat sections using anti-CD68 and major histocompatibility complex (MHC) class II antibodies. Pancreatic exocrine-to-endocrine Reg1 and Reg3β mRNA ratios were markedly increased in Wistar vs GK rats. Conversely, both genes were upregulated in isolated GK rat islets. These findings were unexpected, because Reg genes are expressed in the pancreatic acinar tissue. However, we observed REG-1 protein labeling in acinar peri-ductal tissue close to islets and around large, often disorganized, GK rat islets, which may retain acinar cells due to their irregular shape. These large islets also showed peri-islet macrophage infiltration and increased release of various cytokines/chemokines, particularly IL-6. Thus, IL-6 might potentially trigger acinar REG-1 expression and secretion in the vicinity of large diabetic GK rat islets. This increased acinar REG-1 expression might reflect an adaptive though unsuccessful response to deleterious microenvironment.
Highlights
The pathological roles of inflammatory-mediated mechanisms in type 2 diabetes are emerging from clinical and experimental studies [1]
We show by quantitative RT-PCR that the abundance of transcripts encoding REG-1 ( called pancreatic stone protein-1 (PSP) or lithostathine) and REG-3b ( called pancreatitis associated proteins’ (PAP), PAP-I, hepatocarcinoma-intestine-pancreas (HIP), REG-2 or peptide 23) appeared to be markedly and unexpectedly upregulated in GK rat islets vs control islets
We demonstrate that acinar peri-islet REG-1 labeling characterizes large, often disorganized GK rat islets, which exhibit concomitant peri-islet macrophage infiltration and higher release of cytokine/chemokine CCL3 (MIP-1a) and IL-6, a typical REG/Reg gene family inducer [6,21,22]
Summary
The pathological roles of inflammatory-mediated mechanisms in type 2 diabetes are emerging from clinical and experimental studies [1]. We previously demonstrated pancreatic islet inflammation in the GK rat model of spontaneously occurring type 2 diabetes, as well as in other animal models of spontaneous and/or induced type 2 diabetes and in patients [2,3,4]. Indices of islet inflammation in GK rats were first demonstrated by a transcriptome (Affymetrix) analysis and immunohistochemistry. Upregulated expression of numerous inflammatory genes and increased numbers of macrophages were observed in 4-month-old GK rats, i.e., after 3 months of chronic mild hyperglycemia, vs age-matched Wistar controls [2,3,4]. Islets of younger (2-month-old) diabetic GK rats exhibited high CCL2
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