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