Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells
Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells
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DOI：
10.1016/j.freeradbiomed.2016.08.026
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发表时间：
2016-10-01
影响因子：
7.4
通讯作者：
Devadas, Satish
中科院分区：
文献类型：
--
作者：
Abimannan, Thiruvaimozhi;Peroumal, Doureradjou;Devadas, Satish
活性氧（ROS）信号在辅助性T细胞（Th）分化中起关键作用；但其在分化的Th细胞功能中的作用尚不清楚。在本研究中，我们利用促氧化剂铅白丹素（PB）和过氧化氢研究了氧化应激对类风湿关节炎患者体外分化小鼠Th17和Thl细胞或CD4(+) T细胞效应功能的影响。我们发现，在小鼠Th细胞中，无毒浓度的促氧化剂通过降低Thl细胞中各自的TFs、ROR γ t和t -bet的表达，抑制Thl细胞中IL 17A和ifn - γ的再激活诱导表达。有趣的是，在这两个亚群中，PB通过增强再激活诱导的ERK1/2磷酸化来增加IL-4的表达。我们进一步研究了PB对类风湿关节炎患者外周血中分离的CD4(+) T细胞的细胞因子调节作用，类风湿关节炎是一种众所周知的Th17和/或Thl介导的疾病。在类风湿关节炎患者的CD4- T细胞中，PB降低了IL-17A(+) （Th17）、ifn - γ (+) （Thl）和IL-17A(+)/ ifn - γ (+) （Th17/1）细胞的频率，并抑制了促炎细胞因子TNF-oc和IL-6的产生。抗氧化剂n -乙酰半胱氨酸（NAC）在小鼠和人细胞中完全逆转PB介导的细胞因子调节作用，表明其直接作用于ROS。综上所述，我们的数据表明，氧化微环境可以改变终末分化细胞的细胞因子反应，因此改变细胞内ROS可能是一种靶向自身免疫性疾病中Th17和Thl细胞的潜在方法。(C) 2016年由Elsevier Inc.出版。
Reactive oxygen species (ROS) signaling is critical in T helper (Th) cell differentiation; however its role in differentiated Th cell functions is unclear. In this study, we investigated the role of oxidative stress on the effector functions of in vitro differentiated mouse Th17 and Thl cells or CD4(+) T cells from patients with Rheumatoid Arthritis using pro-oxidants plumbagin (PB) and hydrogen peroxide. We found that in mouse Th cells, non-toxic concentration of pro-oxidants inhibited reactivation induced expression of IL 17A in Th17 and IFN-gamma in Thl cells by reducing the expression of their respective TFs, ROR gamma t and T-bet. Interestingly, in both the subsets, PB increased the expression of IL-4 by enhancing reactivation induced ERK1/2 phosphorylation. We further investigated the cytokine modulatory effect of PB on CD4(+) T cells isolated from PBMCs of patients with Rheumatoid Arthritis, a well-known Th17 and or Thl mediated disease. In human CD4-' T cells from Rheumatoid Arthritis patients, PB reduced the frequencies of IL-17A(+) (Th17), IFN-gamma(+) (Thl) and IL-17A(+)/IFN-gamma(+) (Th17/1) cells and also inhibited the production of pro inflammatory cytokines TNF-oc and IL-6. N-Acetyl Cysteine (NAC) an antioxidant completely reversed PB mediated cytokine modulatory effects in both mouse and human cells indicating a direct role for ROS. Together our data suggest that oxidative microenvironment can alter cytokine response of terminally differentiated cells and thus altering intracellular ROS could be a potential way to target Th17 and Thl cells in autoimmune disorders. (C) 2016 Published by Elsevier Inc.