Journal
CELLS
Volume 7, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/cells7080096
Keywords
1,2-Dichloroethane poisoning; 2-Chloroethanol; matrix metalloproteinases-9; p38 MAPK signal pathway; nuclear factor-kappa B; activator protein-1
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Funding
- National Natural Science Foundation of China [NSFC 81573105, 81172644]
- Program for Liaoning Excellent Talents in University [LR2013038]
- Program for Liaoning Innovative Research Team in University [LT2015028]
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Subacute poisoning of 1,2-dichloroethane (1,2-DCE) has become a serious occupational problem in China, and brain edema is its main pathological consequence, but little is known about the underlying mechanisms. As the metabolite of 1,2-DCE, 2-chloroethanol (2-CE) is more reactive, and might play an important role in the toxic effects of 1,2-DCE. In our previous studies, we found that matrix metalloproteinases-9 (MMP-9) expression was enhanced in mouse brains upon treatment with 1,2-DCE, and in rat astrocytes exposed to 2-CE. In the present study, we analyzed the association of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) with MMP-9 overexpression in astrocytes treated with 2-CE. MMP-9, p65, c-Jun, and c-Fos were significantly upregulated by 2-CE treatment, which also enhanced phosphorylation of c-Jun, c-Fos and inhibitor of kappa B alpha (I kappa B alpha), and nuclear translocation of p65. Furthermore, inhibition of I kappa B alpha phosphorylation and AP-1 activity with the specific inhibitors could attenuate MMP-9 overexpression in the cells. On the other hand, inhibition of p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway suppressed the activation of both NF-kappa B and AP-1 in 2-CE-treated astrocytes. In conclusion, MMP-9 overexpression induced by 2-CE in astrocytes could be mediated at least in part through the p38 signaling pathway via activation of both NF-kappa B and AP-1. This study might provide novel clues for clarifying the mechanisms underlying 1,2-DCE associated cerebral edema.
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