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Cigarette Smoke Decreases Tristetraprolin Expression Through p38-Mediated Pathway
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A2398 - Cigarette Smoke Decreases Tristetraprolin Expression Through p38-Mediated Pathway
Author Block: P. Che, L. Yu, X. Zhao, M. Wang, A. Gaggar, J. E. Blalock, Q. Ding; University of Alabama at Birmingham, Birmingham, AL, United States.
RATIONALE: We have previous shown that Tristetraprolin (TTP) regulates the expression of tumor necrosis factor-alpha (TNF-α), a potent pro-inflammatory mediator, at the post-transcriptional level. TNF-α expression is up-regulated in chronic obstructive pulmonary disease (COPD). Increased TNF-α implies the impaired TTP function. Our work aims to understand whether TTP function is impaired by cigarette smoke and whether this contributes to cigarette smoke induced upregulation of TNF-α expression. METHODS: TTP expression was examined by western blot analysis in murine alveolar macrophages challenged without or with cigarette smoke extract (CSE). p38 expression and activation were also examined. 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, p38 inhibitor was used to evaluate the potential role of p38 in TTP expression in response to CSE. To confirm the findings in vivo, the expression of TTP, TNF-α, and p38 activation were studied in mice exposed to cigarette smoke. RESULTS: CSE induced TTP down-regulation in alveolar macrophages. Reduced TTP expression resulted in significantly increased TNF-α mRNA stability and expression. Importantly, increased TNF-α mRNA stability is result of impaired TTP function in these cells. p38 activity was increased in response to CSE and that is associated with decreased TTP expression. Inhibition of p38 increased TTP expression, leading to decreased TNF-α mRNA stability and expression in CSE treated cells. Cigarette smoke reduced TTP expression, induced p38 activation, and increased TNF-α expression. CONCLUSIONS: The data demonstrate that cigarette smoke exposure reduces TTP expression through a p38-mediated pathway. Impaired TTP function results in significantly increased TNF-α mRNA stability and excessive TNF-α expression in response to CSE.
Author Block: P. Che, L. Yu, X. Zhao, M. Wang, A. Gaggar, J. E. Blalock, Q. Ding; University of Alabama at Birmingham, Birmingham, AL, United States.
RATIONALE: We have previous shown that Tristetraprolin (TTP) regulates the expression of tumor necrosis factor-alpha (TNF-α), a potent pro-inflammatory mediator, at the post-transcriptional level. TNF-α expression is up-regulated in chronic obstructive pulmonary disease (COPD). Increased TNF-α implies the impaired TTP function. Our work aims to understand whether TTP function is impaired by cigarette smoke and whether this contributes to cigarette smoke induced upregulation of TNF-α expression. METHODS: TTP expression was examined by western blot analysis in murine alveolar macrophages challenged without or with cigarette smoke extract (CSE). p38 expression and activation were also examined. 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, p38 inhibitor was used to evaluate the potential role of p38 in TTP expression in response to CSE. To confirm the findings in vivo, the expression of TTP, TNF-α, and p38 activation were studied in mice exposed to cigarette smoke. RESULTS: CSE induced TTP down-regulation in alveolar macrophages. Reduced TTP expression resulted in significantly increased TNF-α mRNA stability and expression. Importantly, increased TNF-α mRNA stability is result of impaired TTP function in these cells. p38 activity was increased in response to CSE and that is associated with decreased TTP expression. Inhibition of p38 increased TTP expression, leading to decreased TNF-α mRNA stability and expression in CSE treated cells. Cigarette smoke reduced TTP expression, induced p38 activation, and increased TNF-α expression. CONCLUSIONS: The data demonstrate that cigarette smoke exposure reduces TTP expression through a p38-mediated pathway. Impaired TTP function results in significantly increased TNF-α mRNA stability and excessive TNF-α expression in response to CSE.
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