Transcriptional Repression of the TGF-{beta} Pseudoreceptor BAMBI by NF-{kappa}B p50 Enhances TGF-{beta} Signaling in Hepatic Stellate Cells [Gene Regulation]

January 21st, 2014 by Liu, C., Chen, X., Yang, L., Kisseleva, T., Brenner, D. A., Seki, E.

TLR4 signaling induces downregulation of BMP and activin membrane bound inhibitor (BAMBI), which enhances TGF-β signaling during hepatic stellate cell (HSC) activation. We investigated the mechanism by which TLR4 signaling downregulates BAMBI expression in HSCs, and found that TLR4- and TNF-α-mediated BAMBI downregulation is dependent on regulation of BAMBI promoter activity through the interaction with NF-κBp50 and HDAC1 in HSCs. Bambi was predominantly expressed in HSCs, at high levels in quiescent HSCs, but at low levels in in vivo-activated and in LPS-stimulated HSCs. In human HSCs, BAMBI expression was downregulated in response to LPS and TNF-α. The BAMBI reporter assay demonstrated that the regulatory element to repress BAMBI transcription is located between 3384 and 1560bp upstream from transcription start site. LPS stimulation downregulated BAMBI expression in cells with NF-κBp65 knockdown, however failed to downregulate BAMBI in cells with inactivation of NF-κB or NF-κBp50 silencing, indicating that NF-κBp50 is a factor for BAMBI downregulation. Chromatin immunoprecipitation (Chip) analysis revealed that LPS and TNF-α induced binding of NF-κBp50:p50 homodimer to the BAMBI promoter region. We also found that HDAC1 is bound to this region as part of the NF-κBp50:HDAC1 complex, repressing transcriptional activity of the BAMBI promoter. Finally, we confirmed that LPS does not repress BAMBI reporter activity using a BAMBI reporter construct with a mutation at 3166bp upstream of the coding region. In summary, our study demonstrates that LPS- and TNF-α-induced NF-κBp50:HDAC1 interaction represses BAMBI transcriptional activity, which contributes to TLR4-mediated enhancement of TGF-β signaling in HSCs during liver fibrosis.
  • Posted in Journal of Biological Chemistry, Publications
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