Phosphodiesterase 4B is essential for T sub(H)2-cell function and development of airway hyperresponsiveness in allergic asthma

• Published in: Journal of allergy and clinical immunology 2010-12, Vol.126 (6), p.1252-1259.e12
• Main Authors: Jin, S-LCatherine, Goya, Sho, Nakae, Susumu, Wang, Dan, Bruss, Matthew, Hou, Chiaoyin, Umetsu, Dale, Conti, Marco
• Format: Article
• Language: English
• ISSN: 0091-6749
• DOI: 10.1016/j.jaci.2010.08.014

Background: Cyclic AMP (cAMP) signaling modulates functions of inflammatory cells involved in the pathogenesis of asthma, and type 4 cAMP-specific phosphodiesterases (PDE4s) are essential components of this pathway. Induction of the PDE4 isoform PDE4B is necessary for Toll-like receptor signaling in monocytes and macrophages and is associated with T cell receptor/CD3 in T cells; however, its exact physiological function in the development of allergic asthma remains undefined. Objectives: We investigated the role of PDE4B in the development of allergen-induced airway hyperresponsiveness (AHR) and T sub(H)2-driven inflammatory responses. Methods: Wild-type and PDE4B super(-/-) mice were sensitized and challenged with ovalbumin and AHR measured in response to inhaled methacholine. Airway inflammation was characterized by analyzing leukocyte infiltration and cytokine accumulation in the airways. Ovalbumin-stimulated cell proliferation and T sub(H)2 cytokine production were determined in cultured bronchial lymph node cells. Results: Mice deficient in PDE4B do not develop AHR. This protective effect was associated with a significant decrease in eosinophils recruitment to the lungs and decreased T sub(H)2 cytokine levels in the bronchoalveolar lavage fluid. Defects in T-cell replication, T sub(H)2 cytokine production, and dendritic cell migration were evident in cells from the airway-draining lymph nodes. Conversely, accumulation of the T sub(H)1 cytokine IFN- gamma was not affected in PDE4B super(-/-) mice. Ablation of the orthologous PDE4 gene PDE4A has no impact on airway inflammation. Conclusion: By relieving a cAMP-negative constraint, PDE4B plays an essential role in T sub(H)2-cell activation and dendritic cell recruitment during airway inflammation. These findings provide proof of concept that PDE4 inhibitors with PDE4B selectivity may have efficacy in asthma treatment.