IRAK-dependent phosphorylation of Stat1 on serine 727 in response to interleukin-1 and effects on gene expression

J Interferon Cytokine Res. 2003 Apr;23(4):183-92. doi: 10.1089/107999003765027384.

Abstract

Interleukin-1 (IL-1) induces the phosphorylation of Stat1 on serine 727 but not on tyrosine 701. Analyses of mutant I1A cells, which lack the IL-1 receptor-associated kinase (IRAK), and of I1A cells reconstituted with deletion mutants of IRAK show that the IL-1-mediated phosphorylation of Stat1 on serine requires the IRAK protein but not its kinase activity and does not involve phosphatidylinositol-3'-kinase (PI3K) or the mitogen-activated protein (MAP) kinases p38 or ERK. IRAK and Stat1 interact in vivo, and this interaction is increased in response to IL-1, suggesting that IRAK may serve to recruit the as yet unknown IL-1-induced Stat1 serine kinase. Chemical inhibitors or dominant-negative forms of signaling components required to activate NF-kappa B, ATF, or AP-1 in response to IL-1 do not affect the phosphorylation of Stat1 on serine. IL-1 and tumor necrosis factor (TNF) enhance the serine phosphorylation of Stat1 that occurs in response to interferon-gamma (IFN-gamma) and potentiate IFN-gamma-mediated, Stat1-driven gene expression, thus contributing to the synergistic activities of these proinflammatory cytokines.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology*
  • Humans
  • Interferon-gamma / pharmacology
  • Interleukin-1 / pharmacology*
  • Interleukin-1 Receptor-Associated Kinases
  • Mice
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Receptors, Interleukin-1 / physiology*
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • STAT1 Transcription Factor
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Interleukin-1
  • Receptors, Interleukin-1
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Stat1 protein, mouse
  • Trans-Activators
  • Phosphoserine
  • Interferon-gamma
  • Protein Kinases
  • Interleukin-1 Receptor-Associated Kinases