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

Repression of the NF-κB pathway has been extensively researched due to its pivotal role in inflammation. We investigated the potential of the aryl hydrocarbon receptor (AHR) to suppress NF-κB 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 ARNT 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/β recruitment to and histone acetylation at Saa3 gene promoter. A battery of acute-phase genes (e.g. 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 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.