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.
Bibliographical noteFunding Information:
The authors thank Jiyeon Jang (Seoul National University College of Medicine) for assisting in the recruitment of human subjects. This study was supported partially by a grant (HI13CO715 to W.-W. L.) from the Korean Health Technology Research and Development Project (Ministry of Health and Welfare, Sejong City, South Korea), and grants (NRF-2018R1A2B2006310 to W.-W.L.; NRF-2013R1A1A2060080 and NRF-2016R1A2B1009767 to H.Y.K.) from the National Research Foundation (Daejeon, South Korea) funded by the Korean government [Ministry of Science and Information and Communications Technology (MSIT). The authors declare no conflicts of interest.
All Science Journal Classification (ASJC) codes
- Molecular Biology