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Originally published In Press as doi:10.1074/jbc.M103235200 on May 7, 2001

J. Biol. Chem., Vol. 276, Issue 28, 25862-25870, July 13, 2001
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SOCS-1 Protein Prevents Janus Kinase/STAT-dependent Inhibition of beta  Cell Insulin Gene Transcription and Secretion in Response to Interferon-gamma *

Sandra CottetDagger , Philippe DuprazDagger , Fabienne Hamburger, Wanda Dolci, Muriel Jaquet, and Bernard Thorens§

From the Institute of Pharmacology and Toxicology, University of Lausanne, 27 Rue du Bugnon, 1005 Lausanne, Switzerland

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)-1beta 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-1beta , 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-1beta 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.

* This work was supported by Juvenile Diabetes Foundation International Grant 4-1999-844 and by Grant 31-46958.96 from the Swiss National Science Foundation (to B. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger These authors contributed equally to this work.

§ To whom correspondence should be addressed: Inst. of Pharmacology and Toxicology, University of Lausanne, 27 rue du Bugnon, 1005 Lausanne, Switzerland. Tel.: 41-21-692-53-90; Fax: 41-21-692-53-55; E-mail: bthorens@ipharm.unil.ch.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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