Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

Cell Mol Life Sci. 2009 Dec;66(23):3787-95. doi: 10.1007/s00018-009-0151-y.

Abstract

Pancreatic beta cell damage caused by proinflammatory cytokines interleukin-1beta (IL-1beta), interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNgamma-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1beta, IFNgamma, TNFalpha. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFNgamma in beta cells. In summary, we show that interference with IFNgamma signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspases / metabolism*
  • Cell Death
  • Cytokines / metabolism
  • Enzyme Activation
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / physiology
  • Interferon-gamma / metabolism
  • Janus Kinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / physiology*

Substances

  • Cytokines
  • Insulin
  • STAT Transcription Factors
  • Socs1 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Nitric Oxide
  • Interferon-gamma
  • Janus Kinases
  • Caspases