Stat1-independent induction of SOCS-3 by interferon-gamma is mediated by sustained activation of Stat3 in mouse embryonic fibroblasts

Biochem Biophys Res Commun. 2005 Feb 18;327(3):727-33. doi: 10.1016/j.bbrc.2004.12.074.

Abstract

Using microarray technology, we previously demonstrated that IFN-gamma induces suppressor of cytokine signaling-3 (SOCS-3) in Stat1-/- mouse embryonic fibroblasts and bone marrow-derived macrophages. In this study, we have investigated the mechanism by which SOCS-3 is induced by Stat1-independent signal transduction pathway. Tyrosine kinases Jak1 and Jak2 are required for SOCS-3 induction by IFN-gamma in mouse embryonic fibroblasts. IFN-gamma stimulated strong and sustained activation of Stat1 whereas Stat3 activation was weak and transient in wild-type fibroblasts. In contrast, Stat3 is activated strongly and in a sustained manner in Stat1-/- fibroblasts. The Src kinase inhibitor SU6656 suppressed IFN-gamma activation of Stat3 in both wild-type and Stat1-/- fibroblasts. However, SU6656 inhibited IFN-gamma induction of SOCS-3 completely in Stat1-/- but not in wild-type fibroblasts. Knock down of Stat3 by short interfering RNA abrogated Stat3 activation and SOCS-3 induction by IFN-gamma in Stat1-/- fibroblasts. In human fibrosarcoma cell line 2fTGH, IFN-gamma activated Stat1 but not Stat3. SOCS-3 induction by IFN-gamma is strictly Stat1-dependent. The Stat1 docking site is required for SOCS-3 induction by IFN-gamma in human lung adenocarcinoma cells. We propose a model in which sustained activation of Stat1 or Stat3 mediates SOCS-3 induction by IFN-gamma in wild-type and Stat1-/- mouse embryonic fibroblasts, respectively.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / metabolism
  • Animals
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Humans
  • Interferon-gamma / metabolism*
  • Lung / cytology
  • Lung / metabolism
  • Mice
  • Molecular Weight
  • Protein-Tyrosine Kinases / metabolism
  • RNA / metabolism
  • Repressor Proteins / metabolism*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • src-Family Kinases / antagonists & inhibitors

Substances

  • DNA-Binding Proteins
  • Repressor Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Socs3 protein, mouse
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • RNA
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • src-Family Kinases