Abstract
RationaleTumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory mediator and its expression is up-regulated in chronic obstructive pulmonary disease (COPD). Tristetraprolin (TTP) is implicated in regulation of TNF-α expression; however, whether TTP is involved in cigarette smoke-induced TNF-α expression has not been determined.MethodsTTP expression was examined by western blot analysis in murine alveolar macrophages and alveolar epithelial cells challenged without or with cigarette smoke extract (CSE). TNF-α mRNA stability, and the decay of TNF-α mRNA, were determined by real-time quantitative RT-PCR. TNF-α protein levels were examined at the same time in these cells. To identify the molecular mechanism involved, a construct expressing the human beta-globin reporter mRNA containing the TNF-α 3’-untranslated region was generated to characterize the TTP targeted site within TNF-α mRNA.ResultsCSE induced TTP down-regulation in alveolar macrophages and alveolar epithelial cells. Reduced TTP expression resulted in significantly increased TNF-α mRNA stability. Importantly, increased TNF-α mRNA stability due to impaired TTP function resulted in significantly increased TNF-α levels in these cells. Forced TTP expression abrogated the increased TNF-α mRNA stability and expression induced by CSE. By using the globin reporter construct containing TNF-α mRNA 3’-untranslated region, the data indicate that TTP directly targets the adenine- and uridine-rich region (ARE) of TNF-α mRNA and negatively regulates TNF-α expression at the post-transcriptional level.ConclusionThe data demonstrate that cigarette smoke exposure reduces TTP expression and impairs TTP function, resulting in significantly increased TNF-α mRNA stability and excessive TNF-α expression in alveolar macrophages and epithelial cells. The data suggest that TTP is a novel post-transcriptional regulator and limits excessive TNF-α expression and inflammatory response induced by cigarette smoke.
Highlights
Cigarette smoke exposure has been firmly associated with the development of chronic obstructive pulmonary disease (COPD) [1,2,3,4]
The data demonstrate that cigarette smoke exposure reduces TTP expression and impairs TTP function, resulting in significantly increased TNF-α mRNA stability and excessive TNFα expression in alveolar macrophages and epithelial cells
The data suggest that TTP is a novel post-transcriptional regulator and limits excessive TNF-α expression and inflammatory response induced by cigarette smoke
Summary
Cigarette smoke exposure has been firmly associated with the development of chronic obstructive pulmonary disease (COPD) [1,2,3,4]. COPD remains a major public health problem in the world and is one major leading cause of chronic morbidity and mortality in the United States [1,2,3,4]. COPD is predicted to become the third leading cause of death by 2020 in the United States and globally according to world health organization. COPD is a progressive lung disease and patients have reduced lung function due to the abnormal permanent enlargement of airspaces and destruction of lung structure [1;4,5,6]. Increased expression of pro-inflammation mediators contributes to persistent inflammation associated with inflammation cell recruitment, epithelial cell death, and abnormal enlargement of airspace in COPD [7;8;11]. Molecular mechanisms leading to the persistent inflammation in COPD lungs have not been completely defined
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