Activin A is an acute allergen-responsive cytokine and provides a link to TGF-β-mediated airway remodeling in asthma

Background: Allergic asthma typically shows activated, allergen-specific CD4⁺ T cells in the early phase and airway remodeling in the late phase of the disease. Although TGF-β plays a crucial role in airway remodeling, it is only marginally induced in CD4⁺ T cells in the early allergen-dependent activation of the immune system. Objective: To elucidate the transition between early- and late-phase events, we investigated the role of activin A, a close family member of TGF-β. Methods: Activin A and TGF-β₁ levels were measured systemically in the serum and in CD4⁺ T cells of asthmatic patients, as well as locally in the lung. Results: Activin A serum levels were increased in patients with severe asthma compared with levels in patients with moderate asthma and healthy control subjects, whereas all patients showed significantly increased TGF-β₁ serum levels independent of disease severity. In T cells only patients with moderate asthma showed increased activin A mRNA expression, whereas TGF-β₁ expression was equal to that seen in healthy subjects. Accordingly, ovalbumin sensitization in a mouse model of allergic asthma could induce activin A mRNA expression, but not TGF-β₁ expression, in the lung. Immunohistochemistry of mice and human specimens revealed an abundant expression of activin A by infiltrating lymphocytes and structural cells of the lung. Although TGF-β₁ more potently enhanced proliferation and Smad 2/3-dependent reporter genes in fibroblasts, activin A was capable of inducing TGF-β₁ and vice versa. Conclusion: Activin A provides a link between acute allergen-specific T-cell responses and chronic TGF-β₁-mediated airway remodeling in asthma.