Abstract
Cigarette smoke is a major cause of chronic obstructive pulmonary disease (COPD) and emphysema. Although cigarette smoke represses cellular proliferation the molecular mechanisms underlying this phenomenon is unknown. CCAAT/enhancer binding proteins (C/EBPs) are key regulators of cell cycle progression, differentiation and pro-inflammatory gene expression, are regulated predominantly at the translational level and may be involved in the pathogenesis of COPD.
Aim of the study was to assess the effect of cigarette smoke on proliferation, the expression and translational regulation of C/EBPα and C/EBPβ, in non-diseased, primary human lung fibroblasts.
Fibroblasts were exposed to cigarette smoke conditioned medium (10% and 20%, 24 hours). Proliferation was determined by [3H]-thymidine incorporation. Protein expression levels were determined by immuno-blotting, and translation was monitored by the novel Translation Control Reporter System (TCRS).
Cigarette smoke significantly reduced fibroblast proliferation and significantly up-regulated full-length C/EBPα and C/EBPβ proteins due to a shift in the translation control of CEBPA and CEBPB mRNAs. This shift involved the re-initiation of mRNA translation via the regulatory upstream open reading frame (uORF), which coincided with increased IL-8 release and decrease of the functional elastin level.
These findings provide a novel mechanism to understand tissue remodeling observed in the lung of COPD patients.
- ERS
