Phosphatase wild-type p53-induced phosphatase 1 controls the development of TH9 cells and allergic airway inflammation

Background: Allergic asthma is one of the most common diseases worldwide, resulting in a burden of diseases. No available therapeutic regimens can cure asthma thus far. Objective: We sought to identify new molecular targets for T(H)9 cell-mediated allergic airway inflammation. Methods: Wild-type p53-induced phosphatase 1 (Wip1) gene knockout mice, Wip1 inhibitor-treated mice, and ovalbumininduced allergic airway inflammation mouse models were used to characterize the roles of Wip1 in allergic airway inflammation. The induction of T-H cell subsets in vitro, real-time PCR, immunoblots, luciferase assays, and chromatin immunoprecipitation assays were used to determine the regulatory pathways of Wip1 in T(H)9 differentiation. Results: Here we demonstrate that Wip1-deficient mice are less prone to allergic airway inflammation, as indicated by the decreased pathologic alterations in lungs. Short-term treatment with a Wip1-specific inhibitor significantly ameliorates allergic inflammation progression. Intriguingly, Wip1 selectively impaired T(H)9 but not T(H)1, T(H)2, and T(H)17 cell differentiation. Biochemical assays show that Wip1 deficiency increases c-Jun/c-Fos activity in a c-Jun N-terminal kinase-dependent manner and that c-Jun/c-Fos directly binds to Il9 promoter and inhibits Il9 transcription. Conclusion: Wip1 controls T(H)9 cell development through regulating c-Jun/c-Fos activity on the Il9 promoter and is important for the pathogenesis of allergic airway inflammation. These findings shed light on the previously unrecognized roles of Wip1 in TH9 cell differentiation. The inhibitory effects of a Wip1 inhibitor on the pathogenesis of allergic airway inflammation can have important implications for clinical application of Wip1 inhibitors in allergy therapies.