title: Cigarette smoke-induced pulmonary inflammatory responses are mediated by EGR-1/GGPPS/MAPK signaling.
abstract: 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.
authors.affiliation: Model Animal Research Center and the School of Medicine, MOE Key Laboratory of Model Animal for Disease Studies, Nanjing University of Nanjing, Nanjing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Shen
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Wang
authors.forename: Fan-Li
authors.initials: FL
authors.lastname: Meng
authors.forename: Long
authors.initials: L
authors.lastname: Qiao
authors.forename: Run-Lin
authors.initials: RL
authors.lastname: Yang
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Pan
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Hua-Qun
authors.initials: HQ
authors.lastname: Chen
authors.forename: Wen
authors.initials: W
authors.lastname: Ning
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*
chemical_list: D051766:Early Growth Response Protein 1; D051231:Farnesyltranstransferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3