title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced inflammatory activation is mediated by intracellular free calcium in microglial cells.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been known to induce inflammatory signaling in a number of cell types and tissues. However, the adverse effects of TCDD on the central nervous system (CNS) have not been entirely elucidated. In this study, using reverse transcriptase PCR (RT-PCR) and ELISA, we showed that TCDD up-regulated the expression and secretion of tumor necrosis factor-alpha (TNF-α) in a time-dependent manner in cultured HAPI microglial cells. TCDD also caused a fast (within 30min as judged by the increase in its mRNA level) activation of cytosolic phospholipase A2 (cPLA2). This initial action was accompanied by up-regulation of cyclooxygenase-2 (COX-2), an important inflammation marker within 1h after TCDD treatment. These pro-inflammatory responses were inhibited by two types of Ca(2+) blockers, bis-(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester (BAPTA-AM) and nifedipine, thus, indicating that the effects are triggered by initial increase in the intracellular concentration of free Ca(2+) ([Ca(2+)]i). Further, TCDD exposure could induce phosphorylation- and ubiquitination-dependent degradation of IкBα, and the translocation of NF-κB p65 from the cytosol to the nucleus in this microglial cell line. Thus, the NF-κB signaling pathway can be activated after TCDD treatment. However, Ca(2+) blockers also obviously attenuated NF-κB activation and transnuclear transport induced by TCDD. In concert with these results, we highlighted that the secretion of pro-inflammatory cytokine and NF-κB activation induced by TCDD can be mediated by elevation of [Ca(2+)]i in HAPI microglial cells.
authors.affiliation: Department of Nutrition and Food Hygieney, School of Public Health, Nantong University, Nantong 226001, Jiangsu, PR China. xugf@ntu.edu.cn
authors.forename: Guangfei
authors.initials: G
authors.lastname: Xu
authors.forename: Yuanye
authors.initials: Y
authors.lastname: Li
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wan
authors.forename: Takeo
authors.initials: T
authors.lastname: Iwata
authors.forename: Noriko
authors.initials: N
authors.lastname: Mizusawa
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Duan
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.forename: Junkang
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D002118:Calcium