International Immunology Advance Access published online on March 22, 2007
International Immunology, doi:10.1093/intimm/dxm026
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An RNA-binding protein 
CP-1 is involved in the STAT3-mediated suppression of NF-
B transcriptional activity
1 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
2 Department of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
Correspondence to: Correspondence to: T. Kobayashi; E-mail: takashik{at}bioreg.kyushu-u.ac.jp
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-
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-
B (NF-B) 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-B reporter activation. The over-expression of STAT3C did not affect the signal transduction of TLR4, such as the phosphorylation of inhibitory nuclear factor-B and mitogen-activated protein kinases and the DNA-binding activity of NF-B. Thus, STAT3C could suppress the transcriptional and/or translational activity of NF-B. To define the molecular mechanism, we searched STAT3C-binding proteins by using a proteomic approach and found that a novel RNA-binding protein, CP-1, interacted with STAT3C. CP-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 CP-1 augmented the suppressive effect of STAT3C on NF-B activation in HEK293/TLR4 cells. Furthermore, the forced expression of CP-1 enhanced the antagonistic effect of IL-10 on IL-6 production in RAW264.7 cells, while small interfering RNA against CP-1 reduced it. These data suggest that CP-1 is involved in the STAT3-mediated suppression of NF-B activity.
Keywords: gene regulation, IL-10, lipopolysaccharide, NF-B, signal transduction, STAT3, Toll-like receptor 4
Transmitting editor: T. Watanabe
Received 4 January 2007, accepted 15 February 2007.
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