title: Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.|Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Xue-Ke
authors.initials: XK
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Pulin
authors.initials: P
authors.lastname: Che
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: Cheng
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Mu
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Oral Surgery, Shanghai Stomatology Hospital, Fudan University, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Infectious Diseases, Public Health Center of Guiyang, Guiyang, Guizhou, China.
authors.forename: Yue-Dong
authors.initials: YD
authors.lastname: Liang
authors.affiliation: Department of Infectious Diseases, People's Hospital of Guizhou Province, Guiyang, Guizhou, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Luo
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Gao
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Wells
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Meng
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Cai
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
authors.affiliation: Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Xiaosi
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Biochemistry, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D045424:Complex Mixtures / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects*; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D012907:Smoking / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051816:Tristetraprolin / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D045424:Complex Mixtures; D012333:RNA, Messenger; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse