SOCS-1 protein prevents Janus kinase/STAT-dependent inhibition of beta cell insulin gene transcription and secretion in response to interferon-gamma

In the pathogenesis of type I diabetes mellitus, activated leukocytes infil trate pancreatic islets and induce beta cell dysfunction and destruction. I nterferon (IFN)-gamma, tumor necrosis factor-ru 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 insuli n synthesis and glucose-stimulated secretion. As described previously IFN-g amma, in combination with IL-1 beta, also induces inducible NO synthase exp ression and apoptosis (Dupraz, P,, Cottet, S,, Hamburger, F., Dolci, W,, Fe lley-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 tra nscription (STAT) pathway in IFN-gamma intracellular signaling, we stably o verexpressed SOCS-1 (suppressor of cytokine signaling-1) in the beta cell l ine. We demonstrated that SOCS-1 suppressed cytokine-induced STAT-1 phospho rylation and increased cellular accumulation, This was accompanied by a sup pression of the effect of IFN-gamma on: (i) reduction in insulin promoter-l uciferase reporter gene transcription, (ii) decrease in insulin mRNA and pe ptide content, and (iii) suppression of glucose-stimulated insulin secretio n, Furthermore, SOCS-1 also suppressed the cellular effects that require th e combined presence of IL-1 beta and IFN-gamma:: induction of nitric oxide production and apoptosis, Together our data demonstrate that IFN-gamma is r esponsible for the cytokine-induced defect in insulin gene expression and s ecretion and that this effect can be completely blocked by constitutive inh ibition of the Janus kinase/STAT pathway.