Expression and functional significance of SOCS-1 and SOCS-3 in astrocytes

J Immunol. 2008 Sep 1;181(5):3167-76. doi: 10.4049/jimmunol.181.5.3167.

Abstract

Astrocytes play a number of important physiological roles in CNS homeostasis. Inflammation stimulates astrocytes to secrete cytokines and chemokines that guide macrophages/microglia and T cells to sites of injury/inflammation. Herein, we describe how these processes are controlled by the suppressor of cytokine signaling (SOCS) proteins, a family of proteins that negatively regulate adaptive and innate immune responses. In this study, we describe that the immunomodulatory cytokine IFN-beta induces SOCS-1 and SOCS-3 expression in primary astrocytes at the transcriptional level. SOCS-1 and SOCS-3 transcriptional activity is induced by IFN-beta through IFN-gamma activation site (GAS) elements within their promoters. Studies in STAT-1alpha-deficient astrocytes indicate that STAT-1alpha is required for IFN-beta-induced SOCS-1 expression, while STAT-3 small interfering RNA studies demonstrate that IFN-beta-induced SOCS-3 expression relies on STAT-3 activation. Specific small interfering RNA inhibition of IFN-beta-inducible SOCS-1 and SOCS-3 in astrocytes enhances their proinflammatory responses to IFN-beta stimulation, such as heightened expression of the chemokines CCL2 (MCP-1), CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL5 (RANTES), and CXCL10 (IP-10), and promoting chemotaxis of macrophages and CD4(+) T cells. These results indicate that IFN-beta induces SOCS-1 and SOCS-3 in primary astrocytes to attenuate its own chemokine-related inflammation in the CNS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / immunology*
  • CD4-Positive T-Lymphocytes / physiology
  • Cells, Cultured
  • Chemokines / genetics
  • Chemotaxis
  • Gene Expression Regulation*
  • Interferon-beta / physiology
  • Macrophages / physiology
  • Mice
  • STAT1 Transcription Factor / physiology*
  • STAT3 Transcription Factor / physiology*
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics*
  • Transcription, Genetic

Substances

  • Chemokines
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Socs1 protein, mouse
  • Socs3 protein, mouse
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Interferon-beta