Mechanisms of allergy and clinical immunology
Phosphodiesterase 4B is essential for TH2-cell function and development of airway hyperresponsiveness in allergic asthma

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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 TH2-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 TH2 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 TH2 cytokine levels in the bronchoalveolar lavage fluid. Defects in T-cell replication, TH2 cytokine production, and dendritic cell migration were evident in cells from the airway-draining lymph nodes. Conversely, accumulation of the TH1 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 TH2-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.

Section snippets

Mice

Generation of PDE4B and PDE4A homozygous null mice was described previously.26, 28 Mice used in this study were 2 to 5 months of age and on a mixed C57BL/6-129/Ola background. In addition, the PDE4B−/− allele was transferred to a pure C57BL/6 background by 12 generations of backcrossing and purity confirmed by single nucleotide polymorphism analysis. The results reported in this article’s Fig E1, Fig E6, Fig E7 in the Online Repository at www.jacionline.org were derived from mice on this pure

PDE4B−/− mice do not develop AHR

To investigate the effect of PDE4B ablation on the development of AHR, C57BL6/129Ola PDE4B−/− mice and wild-type littermates were sensitized intraperitoneally and challenged intranasally with OVA (see Methods). Twenty-four hours after the final allergen exposure, airway responsiveness to increasing concentrations of methacholine was measured by either whole-body plethysmography or invasive methods. Wild-type littermates sensitized and challenged with OVA developed significant AHR (Fig 1, A). In

Discussion

The current studies demonstrate that PDE4B is essential for development of AHR and induction of normal TH2-cell functions in allergen-sensitized mice. Unlike PDE4A or PDE4D, ablation of PDE4B protects mice from developing AHR and leukocyte infiltration to the lungs. Thus, inhibition of a single PDE4 isotype is sufficient to ameliorate the airway inflammation and hyperreactivity associated with allergic asthma.

It is accepted that the TH2 cytokines IL-4, IL-5, and IL-13 are the principal

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  • Cited by (0)

    Supported by the NIH-SCOR center (NIH-HL67674), NIH1R56AI073705-01, and the Sandler Foundation for Asthma Research grants (to M.C.) and a National Science Council grant (NSC98-2320-B-008-001, Taiwan) to S.-L.C. Jin.

    Disclosure of potential conflict of interest: S.-L. C. Jin has received research support from the National Science Council (Taiwan). D. Umetsu has received research support from the National Institutes of Health. M. Conti is a consultant for Pfizer, has received an honorarium from Nycomed, and has received research support from the NIH and the Sandler Foundation. The rest of the authors have declared that they have no conflict of interest.

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