Indoxyl sulfate–induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages

ABSTRACT Indoxyl sulfate (IS) is a uremic toxin associated with increased prevalence of cardiovascular diseases (CVDs) in patients with chronic kidney disease. Despite the crucial role of uremia‐related immune dysfunction, a majority of studies attempting to elucidate its pathogenic role in CVD have focused on IS‐mediated endothelial dysfunction. Thus, we investigated the underlying molecular mechanisms involved in IS‐induced production of TNF‐α, a major cardiotoxic cytokine, by human macrophages. We found that crosstalk between the aryl hydrocarbon receptor (AhR), NF‐κB, and the suppressor of cytokine signaling (SOCS)2 is important for TNF‐α production in IS‐stimulated human macrophages. IS‐activated AhR rapidly associates with the p65 NF‐κB subunit, resulting in mutual inhibition of AhR and NF‐κB and inhibition of TNF‐α production at an early time point. Later, this repression of TNF‐α production is alleviated when SOCS2, a negative modulator of NF‐κB, is directly induced by IS‐activated AhR. In addition, once free of inhibition, activated AhR induces TNF‐α expression by interacting with AhR binding sites in the TNF‐ α gene. Lastly, we confirmed decreased AhR and increased SOCS2 expression in monocytes of patients with end‐stage renal disease, indicating the activation of AhR. Taken together, our results suggest that IS‐induced TNF‐α production in macrophages is regulated through a complicated mechanism involving interaction of AhR, NF‐κB, and SOCS2.—Kim, H. Y., Yoo, T.‐H., Cho, J.‐Y., Kim, H. C., Lee, W.‐W. Indoxyl sulfate‐induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages. FASEB J. 33, 10844–10858 (2019). www.fasebj.org