Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma

J Allergy Clin Immunol. 2009 Sep;124(3):454-62. doi: 10.1016/j.jaci.2009.06.022.


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.

Conclusion: Both TGF-beta and activin signaling pathways are activated on allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / immunology
  • Activin Receptors, Type I / metabolism
  • Activin Receptors, Type II / immunology
  • Activin Receptors, Type II / metabolism
  • Activins / biosynthesis*
  • Adult
  • Allergens / immunology*
  • Asthma / immunology*
  • Bronchial Provocation Tests*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cytokines / immunology
  • Cytokines / metabolism
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Follistatin / immunology
  • Follistatin / metabolism
  • Follistatin / pharmacology
  • Humans
  • Interleukin-13 / pharmacology
  • Middle Aged
  • Receptors, Transforming Growth Factor beta / immunology
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Smad2 Protein / immunology
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta / biosynthesis*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Allergens
  • Cytokines
  • Follistatin
  • Interleukin-13
  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • activin A
  • Activins
  • Activin Receptors, Type I
  • Activin Receptors, Type II