title: Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma.
abstract: BACKGROUND
  Both transforming growth factor (TGF)-beta(1) and activin-A have been implicated in airway remodeling in asthma, but the modulation of their specific signaling pathways after disease activation remains undefined.
  
  
  OBJECTIVE
  To define the expression kinetics of TGF-beta(1), activin-A ligands, and follistatin (a natural activin inhibitor), their type I and type II receptors (activin-like kinase[ALK]-1, ALK-5, ALK-4, TbetaRII, and ActRIIA/RIIB) and activation of signaling (via phosphorylated (p) Smad2), in the asthmatic airway after allergen challenge.
  
  
  METHODS
  Immunohistochemistry was performed on bronchial biopsies from 15 mild atopic patients with asthma (median age, 25 years; median FEV(1)% predicted, 97%) at baseline and 24 hours after allergen inhalation. Functional effects of activin-A were evaluated by using cultured normal human bronchial epithelial (NHBE) cells.
  
  
  RESULTS
  pSmad2(+) epithelial cells increased at 24 hours (P = .03), and pSmad2 was detected in submucosal cells. No modulation of activin-A, follistatin, or TGF-beta(1) expression was demonstrated. Activin receptor(+) cells increased after allergen challenge: ALK-4 in epithelium (P = .04) and submucosa (P = .04), and ActRIIA in epithelium (P = .01). The TGF-beta receptor ALK-5 expression was minimal in the submucosa at baseline and after challenge and was downregulated in the epithelium after challenge (P = .02), whereas ALK-1 and TbetaRII expression in the submucosa increased after allergen challenge (P = .03 and P = .004, respectively). ALK-1 and ALK-4 expression by T cells was increased after allergen challenge. Activin-A induced NHBE cell proliferation, was produced by NHBE cells in response to TNF-alpha, and downregulated TNF-alpha and IL-13-induced chemokine production by NHBE cells.
  
  
  CONCLUSIONS
  Both TGF-beta and activin signaling pathways are activated on allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.
authors.affiliation: Allergy and Clinical Immunology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Harsha H
authors.initials: HH
authors.lastname: Kariyawasam
authors.forename: Sophie
authors.initials: S
authors.lastname: Pegorier
authors.forename: Julia
authors.initials: J
authors.lastname: Barkans
authors.forename: Georgina
authors.initials: G
authors.lastname: Xanthou
authors.forename: Maxine
authors.initials: M
authors.lastname: Aizen
authors.forename: Sun
authors.initials: S
authors.lastname: Ying
authors.forename: A Barry
authors.initials: AB
authors.lastname: Kay
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Robinson
mesh_terms: D030201:Activin Receptors, Type I / Q000276:immunology / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000276:immunology / Q000378:metabolism; D028341:Activins / Q000096:biosynthesis*; D000328:Adult; D000485:Allergens / Q000276:immunology*; D001249:Asthma / Q000276:immunology*; D001985:Bronchial Provocation Tests; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D038681:Follistatin / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D008875:Middle Aged; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051899:Smad2 Protein / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000485:Allergens; D016207:Cytokines; D038681:Follistatin; D018793:Interleukin-13; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C422405:activin A; D028341:Activins; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II