Upregulation of Matrix Metalloproteinase-9 in Primary Cultured Rat Astrocytes Induced by 2-Chloroethanol Via MAPK Signal Pathways

Abstract

2-Chloroethanol (2-CE) is one of the reactive metabolites of 1,2-DCE in vivo, which might contribute to brain edema formation induced by 1,2-dichloroethane (1,2-DCE) poisoning. Thus, the purpose of this study was to explore the roles of mitogen-activated protein kinase (MAPK) signal pathways in upregulation of matrix metalloproteinase-9 (MMP-9) in 2-CE exposed rat astrocytes. Expression of p38 MAPK (p38), extracellular signal regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and MMP-9 at both protein and gene levels in rat astrocytes were determined using western blot and real-time RT-PCR methods. The results showed that both protein and mRNA levels of MMP-9 in 2-CE exposed astrocytes significantly increased. Meanwhile, protein levels of phosphorylated p38 (p-p38), ERK1/2 (p-ERK1/2) and JNK1/2 (p-JNK1/2) in 2-CE exposed astrocytes also significantly increased. In addition, both protein and mRNA levels of MMP-9 significantly decreased in response to reduced protein levels of p-p38, p-ERK1/2 and p-JNK1/2 achieved by supplement with their specific inhibitors, indicating that activation of MAPK signal pathways might play an important role in upregulation of MMP-9 expression at the transcriptional level in 2-CE exposed astrocytes. Furthermore, since pretreatment of n-acetyl-l-cysteine (NAC), a powerful antioxidant amino acid, could attenuate the elevated levels of MMP-9, p-p38, p-ERK2 and p-JNK1/2 in 2-CE exposed astrocytes, activation of MAPK signal pathways in 2-CE exposed astrocytes could be mediated partially by reactive oxygen species (ROS), which was most likely generated in the metabolism of 2-CE.

Pomegranate extract inhibits migration and invasion of oral cancer cells by downregulating matrix metalloproteinase‐2/9 and epithelial‐mesenchymal transition

“…A number of studies have demonstrated that MAPKs regulate the MMP‐2/‐9 activation, leading to regulatory cell migration and invasion 48,49 . Our results show that the effects of POMx are mediated by activating ERK1/2 signaling, but not by the JNK and p38 signaling (Figure 7).…”

Disruption of Intracellular ATP Generation and Tight Junction Protein Expression during the Course of Brain Edema Induced by Subacute Poisoning of 1,2-Dichloroethane

“…It is well known that up-regulated expression of MMP-9 could contribute to disruption of the blood brain barrier integrity. Moreover, findings from our studies have disclosed that activated Mitogen Activated Protein Kinase (MAPK) signal pathways were implicated in the modulation of proinflammatory factors, such as MMPs, iterleukins and tumor necrosis factor, AQPs, tight junction proteins during course of brain edema induced 1,2-DCE poisoning (Sun et al, 2016a ; Wang et al, 2017 ).…”

Mitogen-activated protein kinase signaling pathway in oral cancer (Review)

“…The process of tumor invasion relies on the precise coordination of extracellular matrix adhesion and hydrolysis in association with two members of the matrix metalloproteinase (MMP) family; namely MMP-2 and MMP-9. The expression of MMPs is primarily controlled by MAPK and other signaling pathways, including the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway (46). This has been validated by a number of studies in which the inhibitory functions of anticancer drugs on tumor invasion and metastasis were demonstrated to occur by downregulating the MAPK signaling pathway, which resulted in reduced expressions of MMPs (47,48).…”