title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes astrocyte activation and the secretion of tumor necrosis factor-α via PKC/SSeCKS-dependent mechanisms.
abstract: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental pollutant that could induce significant toxic effects in the human nervous system. However, the underlying molecular mechanism has not been entirely elucidated. Reactive astrogliosis has implicated in various neurological diseases via the production of a variety of pro-inflammatory mediators. Herein, we investigated the potential role of TCDD in facilitating astrocyte activation and the underlying molecular mechanisms. We showed that TCDD induced rapid astrocyte activation following TCDD exposure, which was accompanied by significantly elevated expression of Src-Suppressed-C Kinase Substrate (SSeCKS), a protein involved in protein kinase C (PKC)-mediated Nuclear Factor kappa B signaling, suggesting a possible involvement of PKC-induced SSeCKS activation in TCDD-triggered reactive astroglia. In keeping with the finding, we found that the level of phosphorylated Nuclear Factor kappa B p65 was remarkably increased after TCDD treatment. Furthermore, interference of SSeCKS attenuated TCDD-induced inducible nitric oxide synthase, glial fibrillary acidic protein, phospho-p65 expression, and tumor necrosis factor-α secretion in astrocytes. In addition, pre-treatment with PKC inhibitor also attenuated TCDD-induced astrocyte activation, as well as SSeCKS expression. Interestingly, we found that TCDD treatment could lead to SSeCKS perinuclear localization, which could be abolished after treatment with PKC inhibitor. Finally, we showed that inhibition of PKC activity or SSeCKS expression would impair TCDD-triggered tumor necrosis factor-α secretion. Our results suggested that TCDD exposure could lead to astrocyte activation through PKC/SSeCKS-dependent mechanisms, highlighting that astrocytes might be important target of TCDD-induced neurotoxicity. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits neurotoxic effects. Here, we show TCDD induces pro-inflammatory responses in astrocytes. TCDD initiates an increase of [Ca2+]i, followed by the activation of PKC, which then induces the activation of Src-suppressed C-kinase substrate (SSeCKS). SSeCKS promotes NF-κB activation and the secretion of TNF-α and nitric oxide in astrocytes.
authors.affiliation: Department of Nutrition and Food Hygieney, School of Public Health, Nantong University, Nantong, Jiangsu, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Nie
authors.forename: Tao
authors.initials: T
authors.lastname: Tao
authors.forename: Wenbo
authors.initials: W
authors.lastname: Qian
authors.forename: Shengyang
authors.initials: S
authors.lastname: Jiang
authors.forename: Junkang
authors.initials: J
authors.lastname: Jiang
authors.forename: Aihong
authors.initials: A
authors.lastname: Li
authors.forename: Aisong
authors.initials: A
authors.lastname: Guo
authors.forename: Guangfei
authors.initials: G
authors.lastname: Xu
authors.forename: Qiyun
authors.initials: Q
authors.lastname: Wu
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D061251:Primary Cell Culture; D011493:Protein Kinase C / Q000502:physiology*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; C102361:Akap12 protein, rat; D018797:Cell Cycle Proteins; D016207:Cytokines; D004785:Environmental Pollutants; D016328:NF-kappa B; D000072317:Polychlorinated Dibenzodioxins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C
keywords: NF-κB; SSeCKS; TCDD; TNF-α; astrocytes