Cigarette smoke-induced pulmonary inflammatory responses are mediated by EGR-1/GGPPS/MAPK signaling

Ning Shen, Tao Gong, Jian-Dong Wang, Fan-Li Meng, Long Qiao, Run-Lin Yang, Bin Xue, Fei-Yan Pan, Xiao-Jun Zhou, Hua-Qun Chen, Wen Ning, Chao-Jun Li
American Journal of Pathology 2011, 178 (1): 110-8
Early growth response 1 (EGR-1) contributes to the development of chronic obstructive pulmonary disease in the lungs of smokers by mediating pulmonary inflammatory responses, but the direct downstream genes of EGR-1 that regulate this process remain unknown. We show that a new EGR-1 target gene, geranylgeranyl diphosphate synthase (GGPPS), which controls protein prenylation, can regulate the proinflammatory function of EGR-1 by activating MAPK signaling. When C57BL/6 mice were exposed to cigarette smoke, EGR-1 and GGPPS levels increased in their lungs, and the inflammatory responses were augmented, whereas these effects could be reversed by the down-regulation of EGR-1 transcription activity. The accumulation of EGR-1 and GGPPS was induced by MAPK/ERK pathway activation when Beas-2B human bronchial epithelial cells were exposed to cigarette smoke extract (CSE). Further examination showed that EGR-1 in turn regulated Erk1/2 activity because inhibition of EGR-1 transcription activity decreased CSE-induced Erk1/2 phosphorylation. Furthermore, EGR-1-promoted Erk1/2 activation was dependent on GGPPS transcription. Knockdown of GGPPS expression with small-interfering RNA abolished the EGR-1-activated Erk1/2 activity. Both EGR-1 transcription inhibition and GGPPS expression knockdown decreased the inflammatory response induced by CSE in Beas-2B cells. Our results reveal a new EGR-1/GGPPS/MAPK signaling pathway that controls cigarette smoke-induced pulmonary inflammation, and this may shed light on our understanding of the mechanism of cigarette smoke-related pulmonary diseases such as chronic obstructive pulmonary disease.

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