Tetrachlorobenzoquinone exerts neurological pro-inflammatory activity by promoting HMGB1-TLR4 signaling

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• 英文论文题名：Tetrachlorobenzoquinone exerts neurological pro-inflammatory activity by promoting HMGB1-TLR4 signaling
• 论文作者：Juanli Fu ; Yang Song
• 英文论文作者：Juanli Fu ; Yang Song ; College of Pharmaceutical Sciences ; Southwest University
• 年：2016
• 作者机构：College of Pharmaceutical Sciences,Southwest University;
• 英文论文关键词：Tetrachlorobenzoquinone ; neurotoxicity ; inflammation
• 会议召开时间：2016-07-01
• 会议录名称：中国化学会第30届学术年会摘要集-第二十六分会：环境化学
• 语种：英文
• 分类号：R114
• 学会代码：ZGHY
• 会议名称：中国化学会第30届学术年会-第二十六分会 ; 环境化学
• 会议地点：中国辽宁大连
• 主办单位：中国化学会
• 学会名称：中国化学会
• 页数：2
• 文件大小：302k
• 原文格式：D
• 会议级别：全国

摘要

Pentachlorophenol(PCP) has been extensively used as herbicide and insecticide in the agriculture and industry due to its broad applicability,however,PCP has been listed as a group 2B(possibly carcinogenic to humans) carcinogen by the International Agency for Research on Cancer(IARC) and a group B2 carcinogen(probable human carcinogen) by Environmental Protection Agency(EPA).TCBQ is an oxidative metabolite of pentachlorophenol [1].TCBQ,also known as chloranil,is a widely used fungicide as well.Thus,TCBQ may pose a considerable humans and environmental health risk.Although PCP has been extensively investigated,the toxic mode-of-action of TCBQ has not been unveiled.The Toll-like receptors(TLRs) play a crucial role in the molecular mechanisms of inflammatory processes[2].After binding to their corresponding ligands,TLR signaling pathways initiates from the cytoplasmic TIR domains,and subsequently triggers the activation of downstream signaling.Upon stimulation,My D88 recruits IL-1 receptor-associated kinase(IRAK) to TLRs,which in turn leads to the activation of NF-κB,the mitogen-activated protein kinase(MAPK) transduction cascades.High mobility group protein box 1(HMGB1) is a potent agonist at multiple TLR receptors(TLR2,TLR4 and TLR9) and the receptor for advanced glycation end-products(RAGE),which is capable of conveying danger or damage-related signaling after release from immune,activated or neurotic cells[3].HMGB1 has been shown to be a mediator of inflammation in various models of chronic inflammation.Currently,the information of TCBQ-induced neurotoxicity is not available.Here,we selected PC12 cell line,a well-established in vitro model for this assessment.In our study,TCBQ elevated the level of pro-inflammatory cytokines(TNF-α,IL-1β and IL-6) expressions(Fig.1).TCBQ increased protein expressions of TLR4,My D88 and melatonin exhibited a statistically inhibitory effect(Fig.2).Our results clearly exhibited the decreased IκBα level and increased p-IκBα levels in TCBQ-treated PC12 cell.Furthermore,our results showed that the p-p65,p65 and was up-regulated by TCBQ treatment(Fig.3).More over TCBQ markedly induced the phosphorylation of p38,JNK and ERK1/2 MAPKs.However,these increases were attenuated by melatonin treatment(Fig.4).By an immunofluorescent staining assay,the translocation of endogenous HMGB1 was observed after TCBQ treatment(Fig.5).Our data indicate that TCBQ exerts pro-inflammatory activity by promoting HMGB1 release,which induces TLR4 signaling in PC12 cells.
Pentachlorophenol(PCP) has been extensively used as herbicide and insecticide in the agriculture and industry due to its broad applicability,however,PCP has been listed as a group 2B(possibly carcinogenic to humans) carcinogen by the International Agency for Research on Cancer(IARC) and a group B2 carcinogen(probable human carcinogen) by Environmental Protection Agency(EPA).TCBQ is an oxidative metabolite of pentachlorophenol [1].TCBQ,also known as chloranil,is a widely used fungicide as well.Thus,TCBQ may pose a considerable humans and environmental health risk.Although PCP has been extensively investigated,the toxic mode-of-action of TCBQ has not been unveiled.The Toll-like receptors(TLRs) play a crucial role in the molecular mechanisms of inflammatory processes[2].After binding to their corresponding ligands,TLR signaling pathways initiates from the cytoplasmic TIR domains,and subsequently triggers the activation of downstream signaling.Upon stimulation,My D88 recruits IL-1 receptor-associated kinase(IRAK) to TLRs,which in turn leads to the activation of NF-κB,the mitogen-activated protein kinase(MAPK) transduction cascades.High mobility group protein box 1(HMGB1) is a potent agonist at multiple TLR receptors(TLR2,TLR4 and TLR9) and the receptor for advanced glycation end-products(RAGE),which is capable of conveying danger or damage-related signaling after release from immune,activated or neurotic cells[3].HMGB1 has been shown to be a mediator of inflammation in various models of chronic inflammation.Currently,the information of TCBQ-induced neurotoxicity is not available.Here,we selected PC12 cell line,a well-established in vitro model for this assessment.In our study,TCBQ elevated the level of pro-inflammatory cytokines(TNF-α,IL-1β and IL-6) expressions(Fig.1).TCBQ increased protein expressions of TLR4,My D88 and melatonin exhibited a statistically inhibitory effect(Fig.2).Our results clearly exhibited the decreased IκBα level and increased p-IκBα levels in TCBQ-treated PC12 cell.Furthermore,our results showed that the p-p65,p65 and was up-regulated by TCBQ treatment(Fig.3).More over TCBQ markedly induced the phosphorylation of p38,JNK and ERK1/2 MAPKs.However,these increases were attenuated by melatonin treatment(Fig.4).By an immunofluorescent staining assay,the translocation of endogenous HMGB1 was observed after TCBQ treatment(Fig.5).Our data indicate that TCBQ exerts pro-inflammatory activity by promoting HMGB1 release,which induces TLR4 signaling in PC12 cells.

引文

[1]YADID I,RUDOLPH J,HLOUCHOVA K et al.Sequestration of a highly reactive intermediate in an evolving pathway for degradation of pentachlorophenol.Proc Natl Acad Sci U S A,2013,110:E2182-90.
    [2]Tsan,M.F.Toll-like receptors,inflammation and cancer.Semin Cancer Biol,2006,16:32-37.
    [3]Yang,H.,Hreggvidsdottir,H.S.,Palmblad,K.,Wang,H.,Ochani,M.,Li,J.,Lu,B.,Chavan,S.,Rosas-Ballina,M.,Al-Abed,Y.,Akira,S.,Bierhaus,A.,Erlandsson-Harris,H.,Andersson,U.,and Tracey,K.J.A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release.Proc Natl Acad Sci U S A,2010,107:11942-11947.