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