| Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma. | |
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MedLine Citation:
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PMID: 21047676 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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-γ 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. |
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Authors:
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S-L Catherine Jin; Sho Goya; Susumu Nakae; Dan Wang; Matthew Bruss; Chiaoyin Hou; Dale Umetsu; Marco Conti |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-11-03 |
Journal Detail:
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Title: The Journal of allergy and clinical immunology Volume: 126 ISSN: 1097-6825 ISO Abbreviation: J. Allergy Clin. Immunol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-07 Completed Date: 2011-04-05 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 1275002 Medline TA: J Allergy Clin Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 1252-9.e12 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved. |
Affiliation:
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Department of Life Sciences, National Central University, Jhongli. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Asthma / enzymology*, genetics, immunology* Bronchial Hyperreactivity / prevention & control Cell Movement / genetics Cell Proliferation Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics, immunology, metabolism* Cytokines / genetics, immunology, metabolism* Dendritic Cells / immunology, metabolism, pathology Eosinophils / immunology, metabolism, pathology Humans Lung / pathology Mice Mice, Inbred C57BL Mice, Knockout Th2 Cells / immunology, metabolism*, pathology |
| Grant Support | |
ID/Acronym/Agency:
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1R56AI073705-01/AI/NIAID NIH HHS; HL67674/HL/NHLBI NIH HHS; P50 HL067674-050004/HL/NHLBI NIH HHS; R01 HD052909-06/HD/NICHD NIH HHS; R56 AI073705-01A2/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; EC 3.1.4.17/Cyclic Nucleotide Phosphodiesterases, Type 4 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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