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

Hee Young Kim, Tae Hyun Yoo, Joo Youn Cho, Hyeon Chang Kim, Won Woo Lee

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)10844-10858
Number of pages15
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number10
DOIs
Publication statusPublished - 2019 Oct 1

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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