Peng Wang1, Huiting Su1, Lianjun Zhang2, Hui Chen2, Xuelian Hu2, Fan Yang2, Jun Lv3, Lianfeng Zhang4, Yong Zhao5. 1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China. 2. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. 3. Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing, China. Electronic address: lujun98@ccmu.edu.cn. 4. Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; the Institute of Laboratory Animal Science, Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; and the Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: zhanglf@cnilas.org. 5. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Electronic address: zhaoy@ioz.ac.cn.
Abstract
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 TH9 cell-mediated allergic airway inflammation. METHODS: Wild-type p53-induced phosphatase 1 (Wip1) gene knockout mice, Wip1 inhibitor-treated mice, and ovalbumin-induced allergic airway inflammation mouse models were used to characterize the roles of Wip1 in allergic airway inflammation. The induction of TH cell subsets in vitro, real-time PCR, immunoblots, luciferase assays, and chromatin immunoprecipitation assays were used to determine the regulatory pathways of Wip1 in TH9 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 TH9 but not TH1, TH2, and TH17 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 TH9 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.
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 TH9 cell-mediated allergic airway inflammation. METHODS:Wild-type p53-induced phosphatase 1 (Wip1) gene knockout mice, Wip1 inhibitor-treated mice, and ovalbumin-induced allergic airway inflammationmouse models were used to characterize the roles of Wip1 in allergic airway inflammation. The induction of TH cell subsets in vitro, real-time PCR, immunoblots, luciferase assays, and chromatin immunoprecipitation assays were used to determine the regulatory pathways of Wip1 in TH9 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 TH9 but not TH1, TH2, and TH17 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 TH9 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.