Abstract
In the pathogenesis of type I diabetes mellitus, activated leukocytes infiltrate pancreatic islets and induce beta cell dysfunction and destruction. Interferon (IFN)-gamma, tumor necrosis factor-alpha and interleukin (IL)-1 beta play important, although not completely defined, roles in these mechanisms. Here, using the highly differentiated beta Tc-Tet insulin-secreting cell line, we showed that IFN-gamma dose- and time-dependently suppressed insulin synthesis and glucose-stimulated secretion. As described previously IFN-gamma, in combination with IL-1 beta, also induces inducible NO synthase expression and apoptosis (Dupraz, P., Cottet, S., Hamburger, F., Dolci, W., Felley-Bosco, E., and Thorens, B. (2000) J. Biol. Chem. 275, 37672--37678). To assess the role of the Janus kinase/signal transducer and activator of transcription (STAT) pathway in IFN-gamma intracellular signaling, we stably overexpressed SOCS-1 (suppressor of cytokine signaling-1) in the beta cell line. We demonstrated that SOCS-1 suppressed cytokine-induced STAT-1 phosphorylation and increased cellular accumulation. This was accompanied by a suppression of the effect of IFN-gamma on: (i) reduction in insulin promoter-luciferase reporter gene transcription, (ii) decrease in insulin mRNA and peptide content, and (iii) suppression of glucose-stimulated insulin secretion. Furthermore, SOCS-1 also suppressed the cellular effects that require the combined presence of IL-1 beta and IFN-gamma: induction of nitric oxide production and apoptosis. Together our data demonstrate that IFN-gamma is responsible for the cytokine-induced defect in insulin gene expression and secretion and that this effect can be completely blocked by constitutive inhibition of the Janus kinase/STAT pathway.
Highlights
Development of type I diabetes is initiated by the infiltration of the islets of Langerhans by immune and inflammatory cells
We demonstrated that SOCS-1 suppressed cytokine-induced signal transducer and activator of transcription (STAT)-1 phosphorylation and increased cellular accumulation
We show that the stable expression of SOCS-1 in CDM3D cells blocks IFN-␥-induced STAT-1 phosphorylation and increased cellular accumulation and prevents the negative effect of the cytokine on insulin gene expression and stimulated secretion
Summary
Development of type I diabetes is initiated by the infiltration of the islets of Langerhans by immune and inflammatory cells. In mouse  cells or insulinomas, NO appears to be only one of the mechanisms by which these cells are destroyed [18, 19] Another effect of IFN-␥ is to impair insulin secretion, as shown with rodent islets tested in vitro [12, 20]. IFN-␥ itself has been shown to be a potent inducer of SOCS-1 in a wide variety of cell lines [30, 31], suggesting that SOCS-1 acts as a negative feedback regulator of JAK/STAT signaling. Studies with SOCS-1 knockout mice have revealed its important role in negative regulation of IFN-␥ action; animals deficient in SOCS-1 showed severe defects, the most prominent features being growth retardation, impaired T-cell and B-cell development, excessive IFN-␥ responses, and early mortality [32,33,34,35]
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