Journal
INTERNATIONAL IMMUNOLOGY
Volume 19, Issue 5, Pages 609-619Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxm026
Keywords
-
Categories
Ask authors/readers for more resources
Signal transducer and activator of transcription 3 (STAT3) has been shown to mediate the antiinflammatory effect of IL-10. Activated STAT3 suppresses LPS-induced IL-6, tumor necrosis factor-alpha 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-KB (NF-KB) 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-kappa B reporter activation. The over-expression of STAT3C did not affect the signal transduction of TLR4, such as the phosphorylation of inhibitory nuclear factor-kappa B alpha and mitogen-activated protein kinases and the DNA-binding activity of NF-KB. Thus, STAT3C could suppress the transcriptional and/or translational activity of NF-KB. To define the molecular mechanism, we searched STAT3C-binding proteins by using a proteomic approach and found that a novel RNA-binding protein, alpha CP-1, interacted with STAT3C. alpha-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 alpha CP-1 augmented the suppressive effect of STAT3C on NF-KB activation in HEK293/TLR4 cells. Furthermore, the forced expression of alpha CP-1 enhanced the antagonistic effect of IL-10 on IL-6 production in RAW264.7 cells, while small interfering RNA against alpha CP-1 reduced it. These data suggest that alpha CP-1 is involved in the STAT3-mediated suppression of NF-KB activity.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available