期刊
TOXINS
卷 10, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/toxins10030124
关键词
uremic toxins; indoxyl sulfate; macrophage; aryl hydrocarbon receptor; nuclear factor-kappa B; inflammasome; atherosclerosis; cardiovascular disease
资金
- Japan Society for the Promotion of Science [24790837]
- Grants-in-Aid for Scientific Research [24790837, 15K09249] Funding Source: KAKEN
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)-kappa, 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-1 beta 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-kappa B p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-kappa B. 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-kappa B/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1 beta production, which may explain sustained chronic inflammation in CKD patients.
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