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

Background Both transforming growth factor (TGF)-β1and 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-β1, 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, TβRII, 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 FEV1% 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-β1expression 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-β 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 TβRII expression in the submucosa increased after allergen challenge (P= .03 andP= .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-α, and downregulated TNF-α and IL-13-induced chemokine production by NHBE cells. Conclusion Both TGF-β and activin signaling pathways are activated on allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.