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.

The Aryl Hydrocarbon Receptor and the Nervous System

“…Mechanisms of action: Significant roles in the neurotoxicity of AhR ligands are suspected to be due to the non-genomic pathways that are activated following binding of the ligand to the AhR [ 106 , 107 , 108 ] including NMDA ( N -Methyl- d -Aspartate) excitotoxicity, together with an cytoplasmic increase in calcium, generation of reactive oxygen species (ROS), and induction of p27-Kip1 (see above) [ 109 ]. In rat neuronal hippocampal cells, TCDD triggers a non-genomic pathway, which results in a rapid increase in cytoplasmic Ca 2+ within 30 s. This leads to the stimulation of PKC and an alteration of the mitochondrial membrane potential [ 107 ].…”

“…These divergent responses may be the result of ligand-dependent processes. TCDD also influences the phenotype of astrocytes triggering a cytoplasmic Ca 2+ increase, followed by the rapid expression of Src-suppressed-C kinase substrate (SSeCKS), and subsequently, protein kinase C- and TGF-β-activated kinase 1 (TAK1)-dependent NFkB signaling and TNF-α secretion [ 109 , 135 ]. This pro-inflammatory state might also favor neurotoxicity.…”

Aryl hydrocarbon receptors as potential therapeutic targets

“…The neuroprotective potential of 3,3'-diindolylmethane, a selective AhR modulator, has recently been demonstrated in cellular and animal models of Parkinson's disease, in lipopolysaccharide-induced inflammation and neuronal hypoxia (Rzemieniec et al 2016). Activation of apoptotic signals by AhR ligands, on the other hand, can lead to NMDA (N-Methyl-d-Aspartate) receptor-mediated excitotoxicity, increased levels of calcium in the cytoplasm and oxidative stress (Wan et al 2015). Interestingly, NMDA receptors also modulate the AhR function (Lin et al 2008).…”