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Toxins 2018, 10(3), 124; https://doi.org/10.3390/toxins10030124

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

1
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
2
Department of Clinical Engineering and Medical Technology Faculty Medical Technology, Niigata University of Health and Welfare, Niigata 950-3102, Japan
3
Department of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1247, Japan
4
Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-0841, Japan
*
Author to whom correspondence should be addressed.
Received: 16 February 2018 / Revised: 11 March 2018 / Accepted: 13 March 2018 / Published: 15 March 2018
(This article belongs to the Special Issue Novel Issues in Uremic Toxicity)
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Abstract

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. View Full-Text
Keywords: uremic toxins; indoxyl sulfate; macrophage; aryl hydrocarbon receptor; nuclear factor-κB; inflammasome; atherosclerosis; cardiovascular disease uremic toxins; indoxyl sulfate; macrophage; aryl hydrocarbon receptor; nuclear factor-κB; inflammasome; atherosclerosis; cardiovascular disease
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Wakamatsu, T.; Yamamoto, S.; Ito, T.; Sato, Y.; Matsuo, K.; Takahashi, Y.; Kaneko, Y.; Goto, S.; Kazama, J.J.; Gejyo, F.; Narita, I. Indoxyl Sulfate Promotes Macrophage IL-1β Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated. Toxins 2018, 10, 124.

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