The Potential Role of SOCS-3 in the Interleukin-1β-Induced Desensitization of Insulin Signaling in Pancreatic Beta-Cells

  1. Brice Emanuelli,
  2. Murielle Glondu,
  3. Chantal Filloux,
  4. Pascal Peraldi and
  5. Emmanuel Van Obberghen
  1. From INSERM U145, Faculty of Medicine, Nice, France
  1. Address correspondence and reprint requests to Emmanuel Van Obberghen, INSERM U145, IFR-50, Faculty of Medicine, 06107 Nice Cedex 2. France. E-mail: vanobbeg{at}unice.fr

Abstract

Defects in insulin secretion, resulting from loss of function or destruction of pancreatic β-cells, trigger diabetes. Interleukin (IL)-1β is a proinflammatory cytokine that is involved in type 1 and type 2 diabetes development and impairs β-cell survival and function. Because effective insulin signaling is required for the optimal β-cell function, we assessed the effect of IL-1β on the insulin pathway in a rat pancreatic β-cell line. We show that IL-1β decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1β-dependent nitric oxide (NO) production in RINm5F cells. We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as an insulin action inhibitor, was implicated in the IL-1β inhibitory effect on insulin signaling in these cells. We show that IL-1β increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. Moreover, we find that ectopically expressed SOCS-3 associates with the IR and reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1β treatment in RINm5F cells. We propose that IL-1β decreases insulin action in β-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced β-cell survival.

Footnotes

  • B.E. and M.G. contributed equally to this work. P.P. is currently affiliated with Centre de Biochimie, Nice, France.

    This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted May 25, 2004.
    • Received March 12, 2004.
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