An RNA-binding protein αCP-1 is involved in the STAT3-mediated suppression of NF-κB transcriptional activity

Hitomi Nishinakamura, Yasumasa Minoda, Kazuko Saeki, Keiko Koga, Giichi Takaesu, Masafumi Onodera, Akihiko Yoshimura, Takashi Kobayashi

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Signal transducer and activator of transcription 3 (STAT3) has been shown to mediate the anti-inflammatory effect of IL-10. Activated STAT3 suppresses LPS-induced IL-6, tumor necrosis factor-α and IL-12 gene expression in macrophages and dendritic cells. However, the mechanism of Toll-like receptor (TLR) signal suppression by STAT3 has not been clarified. In this study, we investigated the effect of constitutively activated STAT3 (STAT3C) on LPS-induced nuclear factor-κB (NF-κB) activation. The forced expression of STAT3C in HEK293/TLR4 cells, but neither wild-type STAT3 nor dominant-negative form of STAT3, suppressed LPS-TLR4-mediated NF-κB reporter activation. The over-expression of STAT3C did not affect the signal transduction of TLR4, such as the phosphorylation of inhibitory nuclear factor-κBα and mitogen-activated protein kinases and the DNA-binding activity of NF-κB. Thus, STAT3C could suppress the transcriptional and/or translational activity of NF-κB. To define the molecular mechanism, we searched STAT3C-binding proteins by using a proteomic approach and found that a novel RNA-binding protein, αCP-1, interacted with STAT3C. αCP-1 is a K-homology domain-containing RNA-binding protein with specificity for C-rich pyrimidine tracts. Such proteins play pivotal roles in a broad-spectrum of transcriptional and translational events. The over-expression of αCP-1 augmented the suppressive effect of STAT3C on NF-κB activation in HEK293/TLR4 cells. Furthermore, the forced expression of αCP-1 enhanced the antagonistic effect of IL-10 on IL-6 production in RAW264.7 cells, while small interfering RNA against αCP-1 reduced it. These data suggest that αCP-1 is involved in the STAT3-mediated suppression of NF-κB activity.

Original languageEnglish
Pages (from-to)609-619
Number of pages11
JournalInternational immunology
Volume19
Issue number5
DOIs
Publication statusPublished - 2007 May 1
Externally publishedYes

Keywords

  • Gene regulation
  • IL-10
  • Lipopolysaccharide
  • NF-κB
  • STAT3
  • Signal transduction
  • Toll-like receptor 4

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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