Ah receptor represses acute-phase response gene expression without binding to its cognate response element

Lab Invest. 2009 Jun;89(6):695-707. doi: 10.1038/labinvest.2009.24. Epub 2009 Mar 30.


Repression of the nuclear factor-kappaB (NF-kappaB) pathway has been extensively researched because of its pivotal role in inflammation. We investigated the potential of the aryl hydrocarbon receptor (AHR) to suppress NF-kappaB regulated-gene expression, especially acute-phase genes, such as serum amyloid A (Saa). Using AHR mutants, it was determined that nuclear translocation and heterodimerization with AHR-nuclear translocator are essential, but DNA binding is not involved in AHR-mediated Saa repression. A number of AHR ligands were capable of repressing Saa3 expression. AHR activation leads to a decrease in RELA and C/EBP/beta recruitment to and histone acetylation at Saa3 gene promoter. A battery of acute-phase genes (eg C-reactive protein and haptoglobin) induced by cytokine exposure was repressed by AHR activation in mouse hepatocytes. Dietary exposure to an AHR ligand represses cytokine-induced acute-phase response in the liver. Use of a human liver-derived cell line revealed similar repression of Saa mRNA levels and secreted protein. Repression of AHR expression also enhanced Saa induction in response to cytokines, suggesting that AHR is capable of constitutively repressing Saa gene expression. These results establish a role for AHR in inflammatory signaling within the liver, presenting a new therapeutic opportunity, and signify AHR's ability to function in a DNA-independent manner.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Active Transport, Cell Nucleus
  • Acute-Phase Reaction / immunology
  • Acute-Phase Reaction / metabolism*
  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
  • Cell Line
  • Cell Nucleus / metabolism
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation
  • Hepatocytes / metabolism
  • Humans
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • NF-kappa B / metabolism
  • Protein Multimerization
  • Receptors, Aryl Hydrocarbon / agonists
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / physiology*
  • Response Elements*
  • Serum Amyloid A Protein / metabolism
  • Signal Transduction


  • Cytokines
  • Ligands
  • NF-kappa B
  • Receptors, Aryl Hydrocarbon
  • SAA3P protein, human
  • Serum Amyloid A Protein
  • Aryl Hydrocarbon Receptor Nuclear Translocator