Activation of Egr-1 in Human Lung Epithelial Cells Exposed to Silica through MAPKs Signaling Pathways

Abstract

The alveolar type II epithelial cell, regarded historically as a key target cell in initial injury by silica, now appears to be important in both defense from lung damage as well as elaboration of chemokines and cytokines. The molecular basis for silica-induced epithelial cell injury is poorly understood. In this study we explored the activation of nuclear factor Egr-1 and related signal pathway. Human II alveolar epithelial line A549 cells were exposed to silica for indicated time to assay the expression and activation of Egr-1 and upstream MAPKs. Immunofluorescence, western-blot techniques, RT-PCR, Electrophoretic mobility shift assay (EMSA), transient transfection assay, kinase inhibitor experiments were performed. It was found that the expression of Egr-1 at mRNA and protein level was significantly increased in A549 cells after administration with silica and the activity of Egr-1 peaked by silica treatment for 60 minutes. Furthermore, phosphorylated-ERK1/2, P38 MAPKs (the upstream kinase of Egr-1) ballooned during 15-30minutes, 30-60minutes respectively after silica exposure in A549 cells. By administration of ERK1/2, P38 inhibitor, the expression and transcription of Egr-1 were both markedly decreased. But PKC inhibitor did not prevent the increase of Egr-1. These results indicated Egr-1 played a critical role in silica-induced pulmonary fibrosis in an ERK1/2, P38 MAPKs-dependent manner, which suggests Egr-1 is an essential regulator in silicosis, and underlines a new molecular mechanism for fibrosis induced by silica.

Early Growth Response Protein‐1 Expression by Insulin‐Like Growth Factor‐1 Requires ROS‐Dependent Activation of ERK1/2 and PKB Pathways in Vascular Smooth Muscle Cells

“…A role of ERK1/2 pathway in the upregulation of Egr‐1 expression by Apelin‐13, a ligand for G protein‐coupled receptor, as well as by TNF‐α, has also been demonstrated in VSMC [Goetze et al, ; Liu et al, ]. An involvement of ERK/JNK‐dependent mechanism in mediating Egr‐1 expression in non‐vascular cells in response to epidermal growth factor (EGF) [Gregg and Fraizer, ] and silica dust has also been reported [Chu et al, ]. These findings underscore the importance of MAPK pathways in transducing the signals of various stimuli leading to the enhanced expression of Egr‐1.…”

Arecoline stimulated early growth response‐1 production in human buccal fibroblasts: Suppression by epigallocatechin‐3‐gallate

“…Although there are sparse data describing the cellular localization of Egr‐1 protein, a cytoplasmic activity of Egr‐1 is consistent with a role in transcriptional regulation through binding of co‐factors . Recent study has shown that Egr‐1 expression was increased and partly located in cytoplasm after a 30‐minute treatment with silica in human alveolar epithelial A549 cells . Nevertheless, further studies are needed to elucidate the role(s) of cytoplasmic Egr‐1 expression in the pathogenesis of OSF.…”

“…17 Recent study has shown that Egr-1 expression was increased and partly located in cytoplasm after a 30-minute treatment with silica in human alveolar epithelial A549 cells. 18 Nevertheless, further studies are needed to elucidate the role(s) of cytoplasmic Egr-1 expression in the pathogenesis of OSF.…”

Role of p53–fibrinolytic system cross-talk in the regulation of quartz-induced lung injury

“…Numerous animal studies have shown that silica exposure causes lung inflammation, granuloma formation and emphysema (Lacher et al, 2010;Hnizdo and Vallyathan, 2003;Langley et al, 2010). Prior studies have demonstrated that lung epithelial cells are the primary targets of occupational exposure to silica and showed direct evidence of severe degeneration and damage following silica exposure (Chu et al, 2013;Kaewamatawong et al, 2005). Transmission electron microscopic studies suggest internalization of silica particles by these cells (McCracken et al, 2013).…”