Phosphatase Wip1 controls the development of Th9 cells and allergic airway inflammation

Publication date: Available online 19 July 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Peng Wang, Huiting Su, Lianjun Zhang, Hui Chen, Xuelian Hu, Fan Yang, Jun Lu, Lianfeng Zhang, Yong Zhao
BackgroundAllergic asthma is one of the most common diseases worldwide, resulting in a burden of diseases. No available therapeutic regimens can cure asthma so far.ObjectiveTo identify new molecular targets for Th9 cells-mediated allergic airway inflammation.MethodsWild-type p53-induced phosphatase 1 (Wip1) gene knockout mice, Wip1 inhibitor-treated mice and ovalbumin (OVA)-induced allergic airway inflammation mouse models were employed to characterize the roles of Wip1 in allergic airway inflammation. The induction of Th cell subsets in vitro, real-time PCR, immunoblots, luciferase assay and ChIP assays were employed to determine the regulatory pathways of Wip1 in Th9 differentiation.ResultsWe herein demonstrate that Wip1-deficient mice are less prone to allergic airway inflammation as indicated by the decreased pathological alterations in lungs. Short-term treatment of Wip1-specific inhibitor significantly ameliorates allergic inflammation progression. Intriguingly, Wip1 selectively impaired Th9 cell but not Th1, Th2 and Th17 cell differentiation. Biochemical assays show that Wip1 deficiency increases c-Jun/c-Fos activity in a JNK-dependent manner and that c-Jun/c-Fos directly binds to Il-9 promoter and inhibits Il-9 transcription.ConclusionPhosphatase Wip1 controls Th9 cell development through regulating c-Jun/c-Fos activity on Il-9 promoter and is important for the pathogenesis of allergic airway inflammation. These findings shed lights 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 may have important implications for clinical application of Wip1 inhibitors in allergy therapies.

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Teaser

Phosphatase Wip1 specifically regulates Th9 cell differentiation and Wip1 inhibition may represent a promising strategy to treat allergic airway inflammation.


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