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Published on: June 21, 2016
Ah receptor represses acute-phase response gene expression without binding to its cognate response element
Rushang D Patel1, Iain A Murray, Colin A Flaveny
1Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA.
Summary
The aryl hydrocarbon receptor (AHR) suppresses inflammation by repressing NF-kappaB pathway genes, like serum amyloid A (Saa), in a DNA-independent manner. This discovery offers new therapeutic strategies for liver inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Hepatology
Background:
- Nuclear factor-kappaB (NF-kappaB) pathway activation is central to inflammatory responses.
- Acute-phase genes, such as serum amyloid A (Saa), are key targets in inflammation.
- The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with known roles in xenobiotic metabolism and immune modulation.
Purpose of the Study:
- To investigate the role of the aryl hydrocarbon receptor (AHR) in suppressing NF-kappaB-regulated gene expression, particularly acute-phase genes.
- To elucidate the mechanisms underlying AHR-mediated repression of inflammatory gene expression.
- To explore the therapeutic potential of AHR activation in liver inflammation.
Main Methods:
- Utilized AHR mutants to assess the importance of nuclear translocation, heterodimerization, and DNA binding in AHR-mediated repression.
- Administered various AHR ligands to cell cultures and animal models.
- Analyzed gene expression of acute-phase proteins (e.g., Saa, C-reactive protein, haptoglobin) using molecular techniques.
- Investigated protein recruitment to gene promoters and histone acetylation levels.
- Employed human liver-derived cell lines and mouse hepatocytes.
Main Results:
- AHR activation significantly repressed Saa3 gene expression and other cytokine-induced acute-phase genes in hepatocytes.
- AHR-mediated repression of Saa3 involves decreased recruitment of RELA and C/EBP/beta and reduced histone acetylation at the promoter, independent of DNA binding.
- Dietary exposure to an AHR ligand suppressed the hepatic acute-phase response in vivo.
- Similar repression of Saa mRNA and protein was observed in a human liver cell line.
- Reduced AHR expression enhanced Saa induction, indicating a constitutive repressive role for AHR.
Conclusions:
- AHR plays a significant role in suppressing inflammatory signaling within the liver, specifically targeting NF-kappaB-driven acute-phase gene expression.
- AHR-mediated repression of inflammatory genes occurs through a DNA-independent mechanism.
- AHR activation presents a novel therapeutic avenue for managing liver inflammation.
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