Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression

Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10800-5. doi: 10.1073/pnas.96.19.10800.

Abstract

Interferons (IFNs) inhibit induction by IL-4 of multiple genes in human monocytes. However, the mechanism by which IFNs mediate this inhibition has not been defined. IL-4 activates gene expression by inducing tyrosine phosphorylation, homodimerization, and nuclear translocation of the latent transcription factor, STAT6 (signal transducer and activator of transcription-6). STAT6-responsive elements are characteristically present in the promoters of IL-4-inducible genes. Because STAT6 activation is essential for IL-4-induced gene expression, we examined the ability of type I and type II IFNs to regulate activation of STAT6 by IL-4 in primary human monocytes. Pretreatment of monocytes with IFN-beta or IFN-gamma, but not IL-1, IL-2, macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, IL-6, or transforming growth factor beta suppressed activation of STAT6 by IL-4. This inhibition was associated with decreased tyrosine phosphorylation and nuclear translocation of STAT6 and was not evident unless the cells were preincubated with IFN for at least 1 hr before IL-4 stimulation. Furthermore, inhibition by IFN could be blocked by cotreatment with actinomycin D and correlated temporally with induction of the JAK/STAT inhibitory gene, SOCS-1. Forced expression of SOCS-1 in a macrophage cell line, RAW264, markedly suppressed trans-activation of an IL-4-inducible reporter as well as IL-6- and IFN-gamma-induced reporter gene activity. These findings demonstrate that IFNs inhibit IL-4-induced activation of STAT6 and STAT6-dependent gene expression, at least in part, by inducing expression of SOCS-1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carrier Proteins / metabolism*
  • Cell Line
  • Dactinomycin / pharmacology
  • Humans
  • Interferon-beta / metabolism
  • Interferon-gamma / metabolism*
  • Interferons / metabolism*
  • Interleukin-13 / metabolism
  • Interleukin-4 / metabolism*
  • Interleukin-6 / metabolism*
  • Intracellular Signaling Peptides and Proteins*
  • Kinetics
  • Monocytes / metabolism*
  • Phosphorylation
  • Protein Synthesis Inhibitors / pharmacology
  • Repressor Proteins*
  • STAT6 Transcription Factor
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Time Factors
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / metabolism*
  • Transcription, Genetic
  • Transfection
  • Translocation, Genetic

Substances

  • Carrier Proteins
  • Interleukin-13
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Protein Synthesis Inhibitors
  • Repressor Proteins
  • SOCS1 protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Dactinomycin
  • Interleukin-4
  • Interferon-beta
  • Interferon-gamma
  • Interferons