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Toxins (Basel). 2018 Mar 15;10(3). pii: E124. doi: 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.

Author information

1
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. tkywakamatsu@yahoo.co.jp.
2
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. yamamots@med.niigata-u.ac.jp.
3
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. itotoru.gt@gmail.com.
4
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. yokosato0415@hotmail.com.
5
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. ko.matsu.notre@gmail.com.
6
Department of Clinical Engineering and Medical Technology Faculty Medical Technology, Niigata University of Health and Welfare, Niigata 950-3102, Japan. yoshimitsu2003@gmail.com.
7
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. kanekoy@med.niigata-u.ac.jp.
8
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. gotos@med.niigata-u.ac.jp.
9
Department of Nephrology and Hypertension, Fukushima Medical University, Fukushima 960-1247, Japan. jjkaz@fmu.ac.jp.
10
Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-0841, Japan. gejyo@med.niigata-u.ac.jp.
11
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. naritai@med.niigata-u.ac.jp.

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.

KEYWORDS:

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

PMID:
29543732
PMCID:
PMC5869412
DOI:
10.3390/toxins10030124
[Indexed for MEDLINE]
Free PMC Article

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