title: Critical Role of TAK1-Dependent Nuclear Factor-κB Signaling in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced Astrocyte Activation and Subsequent Neuronal Death.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been recently shown to elicit inflammatory response in a number of cell-types. However, whether TCDD could provoke inflammation in astrocytes, the most abundant glial cells in central nervous system (CNS), remains virtually unknown. In the present study, we showed that TCDD exposure could induce evident astrocyte activation both in vivo and in vitro. Further, we found that TGF-β-activated kinase 1 (TAK1), a critical regulator of NF-κB signaling, was rapidly phosphorylated in the process of TCDD-induced reactive astroglia. Exposure to TCDD led to rapid TAK1 and NF-κB p65 phosphorylation, as well as IKBα degradation. Moreover, blockage of TAK1 using siRNA oligos or TAK1 inhibitor 5Z-7-oxozeaenol significantly attenuated TCDD-induced astrocyte activation as well as the release of TNF-α. Finally, we showed that the conditioned medium of TCDD-treated astrocytes promoted the apoptosis of PC12 neuronal cells, which could be blocked with the pre-treatment of TAK1 inhibitor. Taken together, these findings suggested that TCDD could promote the inflammatory activation of astrocytes through modulating TAK1-NF-κB cascade, implicating that reactive astrocytes might contribute to TCDD-induced adverse effects on CNS system.
authors.affiliation: Department of Nutrition and Food Hygieney, School of Public Health, Nantong University, Nantong, 226001, Jiangsu Province, People's Republic of China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wan
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Junkang
authors.initials: J
authors.lastname: Jiang
authors.forename: Shengyang
authors.initials: S
authors.lastname: Jiang
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Nie
authors.forename: Aihong
authors.initials: A
authors.lastname: Li
authors.forename: Aisong
authors.initials: A
authors.lastname: Guo
authors.forename: Qiyun
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D016328:NF-kappa B / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D016716:PC12 Cells; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051996:Transcription Factor RelA / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D017077:Culture Media, Conditioned; D004785:Environmental Pollutants; D020672:I-kappa B Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D000072317:Polychlorinated Dibenzodioxins; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D000099151:MAP Kinase Kinase Kinase 7