TY - JOUR
T1 - An RNA-binding protein αCP-1 is involved in the STAT3-mediated suppression of NF-κB transcriptional activity
AU - Nishinakamura, Hitomi
AU - Minoda, Yasumasa
AU - Saeki, Kazuko
AU - Koga, Keiko
AU - Takaesu, Giichi
AU - Onodera, Masafumi
AU - Yoshimura, Akihiko
AU - Kobayashi, Takashi
N1 - Funding Information:
We thank Yuuki Kawabata and Tomoko Yoshioka for general assistance. Emiko Fujimoto and Masumi Ohtsu (Technical Support Center, Medical Institute of Bioregulation) for conducting mass spectrometry and DNA sequencing, Makoto Matsumoto (Hyogo College Of Medicine) for EMSA assay and Yukiko Nishi for preparing the manuscript. This work was supported by special grants-in-aid from the Ministry of Education, Science, Technology, Sports and Culture of Japan and from the Japan Diabetes Foundation, the Uehara Memorial Foundation, the Kato Memorial Bioscience Foundation, the Takeda Science Foundation and the Haraguchi Memorial Foundation.
PY - 2007/5
Y1 - 2007/5
N2 - 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.
AB - 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.
KW - Gene regulation
KW - IL-10
KW - Lipopolysaccharide
KW - NF-κB
KW - STAT3
KW - Signal transduction
KW - Toll-like receptor 4
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U2 - 10.1093/intimm/dxm026
DO - 10.1093/intimm/dxm026
M3 - Article
C2 - 17383969
AN - SCOPUS:34249681852
VL - 19
SP - 609
EP - 619
JO - International Immunology
JF - International Immunology
SN - 0953-8178
IS - 5
ER -