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SOCS3 negatively regulates IL-6 signaling in vivo

Ben A Croker1, Danielle L Krebs, Jian-Guo Zhang

  • 1Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, 1G Royal Parade, Parkville, Victoria 3050, Australia.

Nature Immunology
|May 20, 2003
PubMed

Insights

Suppressor of cytokine signaling 3 (SOCS3) normally limits interleukin-6 (IL-6) signaling. Its absence prolongs STAT activation and mimics interferon-gamma (IFN-gamma) responses, revealing reciprocal SOCS1/SOCS3 functions.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Members of the suppressor of cytokine signaling (SOCS) family are critical negative regulators of cytokine signaling pathways.
  • Interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) are key cytokines with distinct signaling mechanisms involving signal transducer and activator of transcription (STAT) proteins.

Purpose of the Study:

  • To investigate the specific role of SOCS3 in regulating IL-6 signaling.
  • To determine if SOCS3 deficiency impacts STAT activation pathways.
  • To elucidate the functional relationship between SOCS3, SOCS1, and their regulation of IL-6 and IFN-gamma signaling.

Main Methods:

  • Conditional gene targeting in mice to generate liver-specific and macrophage-specific Socs3 knockout models.
  • Stimulation of cells with IL-6 and IFN-gamma to assess STAT1 and STAT3 activation.
  • Microarray analysis to compare gene expression patterns in Socs3-deficient livers after IL-6 stimulation.

Main Results:

  • Socs3 deficiency in mice led to prolonged STAT1 and STAT3 activation following IL-6 stimulation.
  • IL-6-induced STAT activation remained normal in Socs1-deficient cells, but IFN-gamma-induced STAT1 activation was prolonged.
  • Gene expression profiles in Socs3-deficient livers stimulated by IL-6 resembled those induced by IFN-gamma.

Conclusions:

  • SOCS3 plays a crucial role in negatively regulating IL-6 signaling by limiting STAT activation.
  • SOCS3 and SOCS1 exhibit reciprocal functions in the regulation of IL-6 and IFN-gamma signaling pathways.
  • SOCS3 is implicated in preventing IFN-gamma-like transcriptional responses upon IL-6 stimulation.

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