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Activin and transforming growth factor-[beta] signaling pathways are activated after allergen challenge in mild asthma.
Kariyawasam, Harsha H. MBBS, PhD a,b,c; Pegorier, Sophie PhD b,c; Barkans, Julia a,b,c; Xanthou, Georgina PhD d; Aizen, Maxine a,b,c; Ying, Sun MD, PhD c; Kay, Barry A. MD, PhD b,c,*; Lloyd, Clare M. PhD b,c; Robinson, Douglas S. MD a,b,c
[Miscellaneous Article] Journal of Allergy & Clinical Immunology. 124(3):454-462, September 2009.

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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, T[beta]RII, 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-[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 T[beta]RII 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.