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dc.contributor.authorZhang Li-Yin
dc.contributor.authorZhan Deng-Lin
dc.contributor.authorChen Yuan-Yuan
dc.contributor.authorWang Wei-Hua
dc.contributor.authorHe Cheng-Yong
dc.contributor.authorLin Yi
dc.contributor.authorLin Yu-Chun
dc.contributor.authorLin Zhong-Ning
dc.date.accessioned2020-10-10T03:14:58Z
dc.date.available2020-10-10T03:14:58Z
dc.date.issued2019-11-22
dc.identifier.citationArchives of toxicology,2019,(11)
dc.identifier.other10.1007/s00204-019-02572-w
dc.identifier.urihttps://dspace.xmu.edu.cn/handle/2288/177578
dc.description.abstractAflatoxin B1 (AFB1), a food contaminant derived from Aspergillus fungi, has been reported to cause hepatic immunotoxicity via inflammatory infiltration and cytokines release. As a pro-inflammatory factor, cyclooxygenase-2 (COX-2) is widely involved in liver inflammation induced by xenobiotics. However, the mechanism by which AFB1-induced COX-2 regulates liver inflammatory injury via hepatocytes-Kupffer cells (KCs) crosstalk remains unclear and requires further elucidation. Here, we established a COX-2 upregulated model with AFB1 treatment in vivo (C57BL/6 mice, 1 mg/kg body weight, i.g, 4 weeks) and in vitro (human liver HepaRG cells, 1 μM for 24 h). In vivo, AFB1-treated mice exhibited NLRP3 inflammasome activation, inflammatory infiltration, and increased recruitment of KCs. In vitro, dephosphorylated COX-2 by protein phosphatase 2A (PP2A)-B55δ promoted NLRP3 inflammasome activation, including mitochondrial translocation of NLRP3, caspase 1 cleavage, and IL-1β release. Moreover, phosphorylated COX-2 at serine 601 (p-COX-2Ser601) underwent endoplasmic reticulum (ER) retention for proteasome degradation. Furthermore, pyroptosis and inflammatory response induced by AFB1 were relieved with COX-2 genetic (siPTGS2) intervention or pharmaceutic (celecoxib, 30 mg/kg body weight, i.g, 4 weeks) inhibition of COX-2 via NLRP3 inflammasome suppression in vivo and in vitro. Ex vivo, in a co-culture system with murine primary hepatocytes and KCs, activated KCs induced by damaged signals from pyroptotic hepatocytes, formed a feedback loop to amplify NLRP3-dependent pyroptosis of hepatocytes via pro-inflammatory signaling, leading to liver inflammatory injury. Taken together, our data suggest a novel mechanism that protein quality control of COX-2 determines the intracellular distribution and activation of NLRP3 inflammasome, which promotes liver inflammatory injury via hepatocytes-KCs crosstalk.
dc.language.isozh_CN
dc.subjectAflatoxin B1
dc.subjectCyclooxygenase-2
dc.subjectKupffer cells
dc.subjectLiver inflammatory injury
dc.subjectNLRP3 inflammasome
dc.subjectProtein phosphatase 2A
dc.titleAflatoxin B1 enhances pyroptosis of hepatocytes and activation of Kupffer cells to promote liver inflammatory injury via dephosphorylation of cyclooxygenase-2: an in vitro, ex vivo and in vivo study.
dc.typeArticle


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