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Peroxisome proliferator-activated receptor gamma negatively regulates IFN-beta production in Toll-like receptor (TLR) 3- and TLR4-stimulated macrophages by preventing interferon regulatory factor 3 binding to the IFN-beta promoter.

Publication ,  Journal Article
Zhao, W; Wang, L; Zhang, M; Wang, P; Zhang, L; Yuan, C; Qi, J; Qiao, Y; Kuo, PC; Gao, C
Published in: J Biol Chem
February 18, 2011

Toll-like receptors 3 and 4 utilize adaptor TRIF to activate interferon regulatory factor 3 (IRF3), resulting in IFN-β production to mediate anti-viral and bacterial infection. Peroxisome proliferator-activated receptor (PPAR)-γ is a ligand-activated transcription factor expressed in various immune cells and acts as a transcriptional repressor to inhibit the transcription of many proinflammatory cytokines. But, the function of PPAR-γ in TLR3- and -4-mediated IFN-β production is not well elucidated. Here, we have analyzed the effect of the PPAR-γ agonists on IFN-β production in peritoneal primary macrophages in response to LPS and poly(I:C). PPAR-γ agonists inhibited LPS and poly(I:C)-induced IFN-β transcription and secretion. siRNA knockdown of PPAR-γ expression and transfection of PPAR-γ expression plasmid demonstrated that PPAR-γ agonist inhibits IFN-β production in a PPAR-γ-dependent manner. The ability of the PPAR-γ agonist to inhibit IFN-β production was confirmed in vivo as mice treated with troglitazone exhibited decreased levels of IFN-β upon LPS and poly(I:C) challenge. Chromatin immunoprecipitation (CHIP) assay and electrophoretic mobility shift assay (EMSA) demonstrated that troglitazone treatment impaired IRF3 binding to the IFN-β promoter. Furthermore, troglitazone could inhibit LPS and poly(I:C)-induced STAT1 phosphorylation and subsequent ISRE activation. These results demonstrate that PPAR-γ negatively regulates IFN-β production in TLR3- and 4-stimulated macrophages by preventing IRF3 binding to the IFN-β promoter.

Duke Scholars

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 18, 2011

Volume

286

Issue

7

Start / End Page

5519 / 5528

Location

United States

Related Subject Headings

  • Troglitazone
  • Transcription, Genetic
  • Toll-Like Receptor 4
  • Toll-Like Receptor 3
  • Thiazolidinediones
  • STAT1 Transcription Factor
  • Protein Binding
  • Promoter Regions, Genetic
  • Poly I-C
  • Phosphorylation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zhao, W., Wang, L., Zhang, M., Wang, P., Zhang, L., Yuan, C., … Gao, C. (2011). Peroxisome proliferator-activated receptor gamma negatively regulates IFN-beta production in Toll-like receptor (TLR) 3- and TLR4-stimulated macrophages by preventing interferon regulatory factor 3 binding to the IFN-beta promoter. J Biol Chem, 286(7), 5519–5528. https://doi.org/10.1074/jbc.M110.149823
Zhao, Wei, Lijuan Wang, Meng Zhang, Peng Wang, Lei Zhang, Chao Yuan, Jianni Qi, Yu Qiao, Paul C. Kuo, and Chengjiang Gao. “Peroxisome proliferator-activated receptor gamma negatively regulates IFN-beta production in Toll-like receptor (TLR) 3- and TLR4-stimulated macrophages by preventing interferon regulatory factor 3 binding to the IFN-beta promoter.J Biol Chem 286, no. 7 (February 18, 2011): 5519–28. https://doi.org/10.1074/jbc.M110.149823.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 18, 2011

Volume

286

Issue

7

Start / End Page

5519 / 5528

Location

United States

Related Subject Headings

  • Troglitazone
  • Transcription, Genetic
  • Toll-Like Receptor 4
  • Toll-Like Receptor 3
  • Thiazolidinediones
  • STAT1 Transcription Factor
  • Protein Binding
  • Promoter Regions, Genetic
  • Poly I-C
  • Phosphorylation