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Inhibition of JAK/STAT pathway restrains TSLP-activated dendritic cells mediated inflammatory T helper type 2 cell response in allergic rhinitis

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Abstract

Thymic stromal lymphopoietin (TSLP) has recently been implicated as a key molecule for initiating allergic rhinitis (AR) at the cell-dendritic cell (DC) interface. Previous studies demonstrated that TSLP activated DCs to express more OX40 ligand (OX40L), which is associated with the initiation of T helper type 2 (Th2) cell responses. STAT phosphorylation has been reported to be promoted by TSLP. Thus, we investigated if the JAK/STAT pathway inhibitor CYT387 could affect TSLP-DC-mediated Th2 cell response in naive T cell and AR mice model. Western blot showed that the levels of phosphorylated JAK1, JAK2, STAT1, STAT3, and STAT5 were increased in TSLP-DCs, which can be offset by CYT387. Flow cytometry indicated that CYT387 had obviously down-regulated the surface maturation co-stimulatory molecules (CD11c, CD80, CD86, and MHCII) in DCs, which were increased by TSLP. Moreover, CYT387 markedly reduced the ability of TSLP-DCs to promote the differentiation of naive CD4+ T cells into IL-4-expressing Th2 cells. The histological examination showed that the CYT387-treated group showed less epithelial disruption, epithelial cell proliferation, and reduced eosinophil infiltration compared with AR group. Western blot and RT-PCR demonstrated that the expression of OX40L was increased in AR mice, but that it was decreased by CYT387. Furthermore, CYT387 treatment resulted in the reduction of IL-4 and IL-5 expression and increased IFN-γ level in AR mice, which was consistent with the levels of intracellular cytokine in Th2 cell. In conclusion, we suggest that blockading the JAK/STAT pathway restrains inflammatory Th2 cell response induced by TSLP-DCs in AR.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81300808, 81200731, 81470031).

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Authors and Affiliations

  1. Department of Otolaryngology Head and Neck Surgery, Xijing Hospital, Fourth Military Medical University, No. 127, Changle West Road, Xi’an, 710032, Shaanxi, People’s Republic of China

    Zhaohui Shi, Min Wang, Xiaocheng Wang, Xiaoyuan Li, Xiaodong Chen & Li Qiao

  2. Senna Otolaryngology Head and Neck Surgery Hospital, No. 808, Cuihua Road, Yanta District, Xi’an, 710061, Shaanxi, People’s Republic of China

    Zhaohui Shi, Xiaoyuan Li & Li Qiao

  3. Department of Otolaryngology Head and Neck Surgery, XiangYa Hospital, Central South University, Changsha, 410008, Hunan, China

    Weihong Jiang

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  1. Zhaohui Shi
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  2. Weihong Jiang
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  3. Min Wang
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  4. Xiaocheng Wang
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  7. Li Qiao
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Correspondence to Li Qiao.

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Zhaohui Shi and Weihong Jiang have contributed equally to this study.

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Shi, Z., Jiang, W., Wang, M. et al. Inhibition of JAK/STAT pathway restrains TSLP-activated dendritic cells mediated inflammatory T helper type 2 cell response in allergic rhinitis. Mol Cell Biochem 430, 161–169 (2017). https://doi.org/10.1007/s11010-017-2963-7

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  • DOI: https://doi.org/10.1007/s11010-017-2963-7

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