Dataset Information
Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma.
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ABSTRACT: 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(H)2-driven inflammatory responses.Methods
Wild-type and PDE4B(-/-) 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(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(H)2 cytokine levels in the bronchoalveolar lavage fluid. Defects in T-cell replication, T(H)2 cytokine production, and dendritic cell migration were evident in cells from the airway-draining lymph nodes. Conversely, accumulation of the T(H)1 cytokine IFN-? was not affected in PDE4B(-/-) 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(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.
SUBMITTER: Jin SL
PROVIDER: S-EPMC3002752 | biostudies-literature | 2010 Dec
REPOSITORIES: biostudies-literature
Publications
Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma.
The Journal of allergy and clinical immunology 20101103 6
<h4>Background</h4>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.<h4>Objective ...[more]