Critical Role of TAK1-Dependent Nuclear Factor-κB Signaling in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced Astrocyte Activation and Subsequent Neuronal Death
- 273 Downloads
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.
KeywordsTCDD TAK1 Activation Astrocytes NF-κB
Aryl hydrocarbon receptor
Aryl hydrocarbon receptor nuclear translocator
Central nervous system
TGF-β activated kinase 1
Astrocyte conditioned medium
Glial fibrillary acidic protein
This work was supported by the National Natural Science Foundation of China (Nos. 21477058, 21077061 and 21277078), and a project funded by the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 13KJB330006).
Conflict of interest
The authors declare no conflict of interest.
- 5.Li Y, Chen G, Zhao J, Nie X, Wan C, Liu J, Duan Z, Xu G (2013) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces microglial nitric oxide production and subsequent rat primary cortical neuron apoptosis through p38/JNK MAPK pathway. ToxicologyGoogle Scholar
- 6.Nie X, Liang L, Xi H, Jiang S, Jiang J, Tang C, Liu X, Liu S, Wan C, Zhao J, Yang J (2014) 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin induces premature senescence of astrocytes via WNT/beta-catenin signaling and ROS production. J Appl Toxicol : JATGoogle Scholar
- 24.Shuto T, Xu H, Wang B, Han J, Kai H, Gu XX, Murphy TF, Lim DJ, Li JD (2001) Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKK alpha/beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proc Natl Acad Sci USA 98:8774–8779PubMedCentralPubMedCrossRefGoogle Scholar
- 42.Figiel I (2008) Pro-inflammatory cytokine TNF-alpha as a neuroprotective agent in the brain. Acta Neurobiol Exp (Wars) 68:526–534Google Scholar