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

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-alpha, a major cardiotoxic cytokine, by human macrophages. We found that crosstalk between the aryl hydrocarbon receptor (AhR), NF-kappa B, and the suppressor of cytokine signaling (SOCS)2 is important for TNF-alpha production in IS-stimulated human macrophages. IS-activated AhR rapidly associates with the p65 NF-kappa B subunit, resulting in mutual inhibition of AhR and NF-kappa B and inhibition of TNF-alpha production at an early time point. Later, this repression of TNF-alpha production is alleviated when SOCS2, a negative modulator of NF-kappa B, is directly induced by IS-activated AhR. In addition, once free of inhibition, activated AhR induces TNF-alpha expression by interacting with AhR binding sites in the TNF-alpha 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-alpha production in macrophages is regulated through a complicated mechanism involving interaction of AhR, NF-kappa B, and SOCS2.-Kim, H. Y., Yoo, T.-H., Cho, J.-Y., Kim, H. C., Lee, W.-W. Indoxyl sulfate-induced TNF-alpha is regulated by crosstalk between the aryl hydrocarbon receptor, NF-kappa B, and SOCS2 in human macrophages.