PMID- 27911957 OWN - NLM STAT- MEDLINE DCOM- 20170630 LR - 20201017 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 12 DP - 2016 TI - Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism. PG - e0167451 LID - 10.1371/journal.pone.0167451 [doi] LID - e0167451 AB - RATIONALE: Tumor necrosis factor-alpha (TNF-alpha) 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-alpha expression; however, whether TTP is involved in cigarette smoke-induced TNF-alpha 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-alpha mRNA stability, and the decay of TNF-alpha mRNA, were determined by real-time quantitative RT-PCR. TNF-alpha 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-alpha 3'-untranslated region was generated to characterize the TTP targeted site within TNF-alpha mRNA. RESULTS: CSE induced TTP down-regulation in alveolar macrophages and alveolar epithelial cells. Reduced TTP expression resulted in significantly increased TNF-alpha mRNA stability. Importantly, increased TNF-alpha mRNA stability due to impaired TTP function resulted in significantly increased TNF-alpha levels in these cells. Forced TTP expression abrogated the increased TNF-alpha mRNA stability and expression induced by CSE. By using the globin reporter construct containing TNF-alpha mRNA 3'-untranslated region, the data indicate that TTP directly targets the adenine- and uridine-rich region (ARE) of TNF-alpha mRNA and negatively regulates TNF-alpha 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-alpha mRNA stability and excessive TNF-alpha expression in alveolar macrophages and epithelial cells. The data suggest that TTP is a novel post-transcriptional regulator and limits excessive TNF-alpha expression and inflammatory response induced by cigarette smoke. FAU - Zhao, Xue-Ke AU - Zhao XK AD - Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China. AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Che, Pulin AU - Che P AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Cheng, Ming-Liang AU - Cheng ML AD - Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China. FAU - Zhang, Quan AU - Zhang Q AD - Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China. FAU - Mu, Mao AU - Mu M AD - Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China. FAU - Li, Hong AU - Li H AD - Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China. FAU - Luo, Yuan AU - Luo Y AD - Department of Oral Surgery, Shanghai Stomatology Hospital, Fudan University, Shanghai, China. FAU - Liang, Yue-Dong AU - Liang YD AD - Department of Infectious Diseases, Public Health Center of Guiyang, Guiyang, Guizhou, China. FAU - Luo, Xin-Hua AU - Luo XH AD - Department of Infectious Diseases, People's Hospital of Guizhou Province, Guiyang, Guizhou, China. FAU - Gao, Chang-Qing AU - Gao CQ AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Jackson, Patricia L AU - Jackson PL AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Wells, J Michael AU - Wells JM AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Zhou, Yong AU - Zhou Y AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Hu, Meng AU - Hu M AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Cai, Guoqiang AU - Cai G AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Thannickal, Victor J AU - Thannickal VJ AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Steele, Chad AU - Steele C AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Blalock, J Edwin AU - Blalock JE AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Han, Xiaosi AU - Han X AD - Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Chen, Ching-Yi AU - Chen CY AD - Department of Biochemistry, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. FAU - Ding, Qiang AU - Ding Q AD - Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. LA - eng GR - R01 HL085324/HL/NHLBI NIH HHS/United States GR - K08 HL123940/HL/NHLBI NIH HHS/United States GR - R01 HL124076/HL/NHLBI NIH HHS/United States GR - R01 HL127338/HL/NHLBI NIH HHS/United States GR - R01 HL077783/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20161202 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Complex Mixtures) RN - 0 (RNA, Messenger) RN - 0 (Tristetraprolin) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Zfp36 protein, mouse) SB - IM MH - Animals MH - Cells, Cultured MH - Complex Mixtures/*toxicity MH - Down-Regulation/*drug effects MH - Epithelial Cells/*metabolism/pathology MH - Humans MH - Macrophages, Alveolar/*metabolism/pathology MH - Mice MH - RNA Stability/*drug effects MH - RNA, Messenger/genetics/*metabolism MH - Respiratory Mucosa/*metabolism/pathology MH - Smoking/genetics/*metabolism/pathology MH - Tristetraprolin/*biosynthesis/genetics MH - Tumor Necrosis Factor-alpha/*biosynthesis/genetics PMC - PMC5135108 COIS- The authors declare no competing interest. EDAT- 2016/12/03 06:00 MHDA- 2017/07/01 06:00 PMCR- 2016/12/02 CRDT- 2016/12/03 06:00 PHST- 2016/08/21 00:00 [received] PHST- 2016/11/14 00:00 [accepted] PHST- 2016/12/03 06:00 [entrez] PHST- 2016/12/03 06:00 [pubmed] PHST- 2017/07/01 06:00 [medline] PHST- 2016/12/02 00:00 [pmc-release] AID - PONE-D-16-33456 [pii] AID - 10.1371/journal.pone.0167451 [doi] PST - epublish SO - PLoS One. 2016 Dec 2;11(12):e0167451. doi: 10.1371/journal.pone.0167451. eCollection 2016.