Shi Dongmei, Wang Qiong, Zheng Hailin, Li Dongmei, Shen Yongnian, Fu Hongjun, Li Tianhang, Mei Huan, Lu Guixia, Qiu Ying, Chen Guanzhi, Liu Weida
Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, PR China; Department of Dermatology, Jining No. 1 People's Hospital, Shandong, PR China.
Department of Mycology, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, PR China.
Int Immunopharmacol. 2016 Sep;38:45-53. doi: 10.1016/j.intimp.2016.05.013. Epub 2016 May 26.
Mounting evidence has suggested that inflammation is associated with IL-6/Stat3 pathway in dendritic cells (DCs) and Th17 cells, which are critical for development of allergic contact dermatitis (ACD). Paeoniflorin (PF) has been clinically proved to be effective in the treatment of inflammatory skin diseases such as ACD. We have previously demonstrated the effect of PF on DCs stimulated with 1-chloro-2,4-dinitrobenze (DNCB) and naïve CD4(+)CD45RA(+) T cells for Th17 cell differentiation. However, whether PF down-regulates IL-6/Stat3 in DCs and Th17 cells remains to be explored. In this study, we show clearly that PF markedly decreases IL-6/Stat3 in DCs stimulated with DNCB at both gene and protein levels compared with control DCs in vitro. Meanwhile, PF up-regulates suppressor of cytokine signaling 3 (Socs3). Such decreased expression of IL-6/Stat3 is abolished in DCs that were transfected with Socs3 short interfering RNA (siRNA). When mice CD4(+)CD45 RA(+) T cells were co-cultured with PF-treated DCs stimulated with/without DNCB, the gene expression of the Th17 cell markers such as retinoic acid-related orphan nuclear hormone receptor γt (RORγt), IL-17A, and IL-23R decreased, in accordance with the less secretions of IL-17 and IL-23 in vitro and in vivo. Finally, the suppressed Th17 differentiation induced by PF can be abolished by additional recombinant mouse IL-6. Our results suggest that the anti-inflammatory mechanisms introduced by depletion of Socs3 expression or inactivation of the negative regulator such as Socs3 may represent a promising strategy for the prevention of ACD.
越来越多的证据表明，炎症与树突状细胞（DCs）和Th17细胞中的IL-6/Stat3信号通路有关，而这两种细胞对过敏性接触性皮炎（ACD）的发展至关重要。芍药苷（PF）已在临床上被证明对治疗诸如ACD等炎症性皮肤病有效。我们之前已经证明了PF对用1-氯-2,4-二硝基苯（DNCB）刺激的DCs以及对Th17细胞分化的初始CD4(+)CD45RA(+) T细胞的作用。然而，PF是否下调DCs和Th17细胞中的IL-6/Stat3仍有待探索。在本研究中，我们清楚地表明，与体外对照DCs相比，PF在基因和蛋白质水平上均显著降低了用DNCB刺激的DCs中的IL-6/Stat3。同时，PF上调细胞因子信号转导抑制因子3（Socs3）。在用Socs3小干扰RNA（siRNA）转染的DCs中，IL-6/Stat3的这种表达降低被消除。当小鼠CD4(+)CD45 RA(+) T细胞与经PF处理的、用/不用DNCB刺激的DCs共培养时，Th17细胞标志物如视黄酸相关孤儿核激素受体γt（RORγt）、IL-17A和IL-23R的基因表达降低，这与体外和体内IL-17和IL-23的分泌减少一致。最后，额外添加重组小鼠IL-6可消除PF诱导的Th17分化抑制。我们的结果表明，通过缺失Socs3表达或使Socs3等负调节因子失活所引入的抗炎机制可能是预防ACD的一种有前景的策略。
