Indoxyl Sulfate Promotes Macrophage IL-1β Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated

Toxins (Basel). 2018 Mar 15;10(3):124. doi: 10.3390/toxins10030124.


In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay. IS induced macrophage pro-IL-1β mRNA expression, although mature IL-1 was only slightly increased. IS increased AhR and the AhR-related mRNA expression; this change was suppressed by administration of proteasome inhibitor. IS promoted phosphorylation of NF-κB p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-κB. In contrast, IS decreased NLRP3 and did not change ASC, pro-caspase 1, or caspase-1 activation. IS-inducing inflammation in macrophages results from accelerating AhR-NF-κB/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1β production, which may explain sustained chronic inflammation in CKD patients.

Keywords: aryl hydrocarbon receptor; atherosclerosis; cardiovascular disease; indoxyl sulfate; inflammasome; macrophage; nuclear factor-κB; uremic toxins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Indican / pharmacology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Signal Transduction
  • THP-1 Cells


  • Interleukin-1beta
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Receptors, Aryl Hydrocarbon
  • Mitogen-Activated Protein Kinases
  • Indican