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

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-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.

• Authors: S-L Catherine Jin, Sho Goya, Susumu Nakae, Dan Wang, Matthew Bruss, Chiaoyin Hou, Dale Umetsu, Marco Conti
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 126 Issue 6 Pg. 1252-9.e12 (Dec 2010) ISSN: 1097-6825 [Electronic] United States
• PMID: 21047676 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Chemical References

• Cytokines
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• 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)