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Indoxyl Sulfate Promotes Macrophage IL-1? Production by Activating Aryl Hydrocarbon Receptor/NF-?/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated #MMPMID29543732
Wakamatsu T; Yamamoto S; Ito T; Sato Y; Matsuo K; Takahashi Y; Kaneko Y; Goto S; Kazama JJ; Gejyo F; Narita I
Toxins (Basel) 2018[Mar]; 10 (3): ä PMID29543732show ga
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)-?, 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? 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-?B p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-?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-?B/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1? production, which may explain sustained chronic inflammation in CKD patients.