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.

GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

“…When we exposed the mice to cigarette smoke for 27 weeks, we found that EGR-1 and GGPPS appeared to be constantly activated and that they promoted inflammatory responses and tissue damage. 26 As a novel EGR-1 target gene, GGPPS may mediate the function of EGR-1 during cigarette smoke exposure by driving sustained ERK 1/2 activation. In addition, the transcription of several other EGR-1 target genes (eg, HO-1, 49 human IL-2, 12 IL-2 receptor, 14 Fas/CD95, 15 and intercellular adhesion molecule 1 16 ) may also be inhibited by the DnEGR-1 adenovirus.…”

“…Thus we have identified a novel feedback pathway that augments EGR-1-induced inflammatory responses in cultured cells and in a mouse model of pulmonary inflammation. 26 This study may provide additional insight into the complex processes that lead to cigarette smoke-related damage to respiratory tissues.…”

Inferring Single Nucleotide Polymorphisms in MicroRNA Binding Sites of Lung Cancer-related Inflammatory Genes

“…Candidate genes are retrieved according to the information from the website (http://www.sabiosciences. com/Cytokines_Inflammation.php), BioCarta and KEGG pathways which are two common databases that provide displays of gene interactions for human cellular processes (http://cgap.nci.nih.gov/Pathways) and literatures (Shen et al, 2011;Yu et al, 2011;McMillan et al, 2011 ;Lee et al, 2012) commonly acknowledged as important inflammatory genes associated with smoking.…”

Protein prenylation and human diseases: a balance of protein farnesylation and geranylgeranylation

“…Furthermore, both Egr-1 and its target genes GGPPS and HO-1 were increasingly expressed in the lung from the cigarette smoke induced COPD mice. GGPPS is the enzyme that prenylates and activates Ras and re-activates the MAPK/Erk1/2, sequentially activates Egr-1 expression in a positive feedback way [23,24]. The constant activated Egr-1 by long-term smoke enhances the inflammation in pulmonary and over-activates the metalloprotease, eventually aggravates the impairment of lung tissue.…”