title: α1-Antitrypsin activates protein phosphatase 2A to counter lung inflammatory responses.
abstract: BACKGROUND
  α1-Antitrypsin (A1AT) was identified as a plasma protease inhibitor; however, it is now recognized as a multifunctional protein that modulates immunity, inflammation, proteostasis, apoptosis, and cellular senescence. Like A1AT, protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, regulates similar biologic processes and plays a key role in chronic obstructive pulmonary disease.
  
  
  OBJECTIVE
  Given their common effects, this study investigated whether A1AT acts via PP2A to alter tumor necrosis factor (TNF) signaling, inflammation, and proteolytic responses in this disease.
  
  
  METHODS
  PP2A activity was measured in peripheral blood neutrophils from A1AT-deficient (PiZZ) and healthy (PiMM) individuals and in alveolar macrophages from normal (60 mg/kg) and high-dose (120 mg/kg) A1AT-treated PiZZ subjects. PP2A activation was assessed in human neutrophils, airway epithelial cells, and peripheral blood monocytes treated with plasma purified A1AT protein. Similarly, lung PP2A activity was measured in mice administered intranasal A1AT. PP2A was silenced in lung epithelial cells treated with A1AT and matrix metalloproteinase and cytokine production was then measured following TNF-α stimulation.
  
  
  RESULTS
  PP2A was significantly lower in neutrophils isolated from PiZZ compared with PiMM subjects. A1AT protein activated PP2A in human alveolar macrophages, monocytes, neutrophils, airway epithelial cells, and in mouse lungs. This activation required functionally active A1AT protein and protein tyrosine phosphatase 1B expression. A1AT treatment acted via PP2A to prevent p38 and IκBα phosphorylation and matrix metalloproteinase and cytokine induction in TNF-α-stimulated epithelial cells.
  
  
  CONCLUSIONS
  Together, these data indicate that A1AT modulates PP2A to counter inflammatory and proteolytic responses induced by TNF signaling in the lung.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Mount Sinai Roosevelt Hospital, New York, New York.
authors.forename: Patrick
authors.initials: P
authors.lastname: Geraghty
authors.forename: Edward
authors.initials: E
authors.lastname: Eden
authors.forename: Manju
authors.initials: M
authors.lastname: Pillai
authors.forename: Michael
authors.initials: M
authors.lastname: Campos
authors.forename: Noel G
authors.initials: NG
authors.lastname: McElvaney
authors.forename: Robert F
authors.initials: RF
authors.lastname: Foronjy
mesh_terms: D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008168:Lung / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects*; D054648:Protein Phosphatase 2 / Q000172:deficiency / Q000187:drug effects* / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology; D015842:Serine Proteinase Inhibitors / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D012907:Smoking / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D054648:Protein Phosphatase 2
keywords: PP2A; cell signaling; inflammation; phosphorylation; α1-antitrypsin