Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism
| Autor: | Chad Steele, Qiang Ding, J. Michael Wells, Yong Zhou, Xiaosi Han, Quan Zhang, Pulin Che, Patricia L. Jackson, Ming-liang Cheng, Hong Li, J. Edwin Blalock, Yue-Dong Liang, Ching Yi Chen, Yuan Luo, Xin-Hua Luo, Victor J. Thannickal, Mao Mu, Meng Hu, Chang-Qing Gao, Guo-Qiang Cai, Xueke Zhao |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pulmonology RNA Stability Tristetraprolin Gene Expression lcsh:Medicine Pathology and Laboratory Medicine Biochemistry Epithelium Mice White Blood Cells Habits 0302 clinical medicine Animal Cells hemic and lymphatic diseases Gene expression Medicine and Health Sciences Smoking Habits Public and Occupational Health Alveolar Macrophages lcsh:Science Immune Response Cells Cultured Multidisciplinary medicine.diagnostic_test Messenger RNA Smoking respiratory system Nucleic acids Tumor necrosis factor alpha medicine.symptom Cellular Types Anatomy Research Article Substance-Related Disorders Immune Cells Chronic Obstructive Pulmonary Disease Immunology Down-Regulation Inflammation Respiratory Mucosa Complex Mixtures 03 medical and health sciences Mediator Signs and Symptoms Western blot Downregulation and upregulation Diagnostic Medicine Macrophages Alveolar Mental Health and Psychiatry medicine Genetics Animals Humans RNA Messenger Behavior Blood Cells business.industry Tumor Necrosis Factor-alpha lcsh:R Biology and Life Sciences Smoking Related Disorders Epithelial Cells Cell Biology 030104 developmental biology Biological Tissue 030228 respiratory system Cancer research RNA lcsh:Q business |
| Zdroj: | PLoS ONE, Vol 11, Iss 12, p e0167451 (2016) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Rationale Tumor 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. Methods TTP 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. Results CSE 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. Conclusion The 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. |
| Databáze: | OpenAIRE |
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