Plumbagin inhibits proliferative and inflammatory responses of T cells independent of ROS generation but by modulating intracellular thiols.
Plumbagin inhibits proliferative and inflammatory responses of T cells independent of ROS generation but by modulating intracellular thiols.
复制标题
DOI：
10.1002/jcb.22620
复制
发表时间：
2010-08-01
影响因子：
4
通讯作者：
Sainis, K. B.
中科院分区：
文献类型：
--
作者：
Checker, Rahul;Sharma, Deepak;Sandur, Santosh K.;Subrahmanyam, G.;Krishnan, Sunil;Poduval, T. B.;Sainis, K. B.
白花丹素通过抑制核因子-κB（NF-κB）抑制淋巴细胞的活化、增殖、细胞因子产生和移植物抗宿主病，并抑制肿瘤细胞的生长。白花丹素还显示通过未知机制诱导肿瘤细胞中的活性氧（ROS）产生。本报告描述了一种新的作用，细胞氧化还原在正常淋巴细胞的免疫反应的调制白花丹素。白花丹素耗尽谷胱甘肽（GSH）水平，导致ROS生成增加。如质谱和HPLC分析所示，GSH水平的降低是由于白花丹素与GSH直接反应所致。此外，向细胞中加入白花丹素导致蛋白质上游离巯基的减少和蛋白质谷胱甘肽化的增加。白花丹素对丝裂原诱导的T细胞增殖和细胞因子（IL-2/IL-4/IL-6/IFN-γ）产生的抑制被硫醇抗氧化剂而不是非硫醇抗氧化剂消除，证实硫醇而不是ROS在白花丹素的生物活性中起重要作用。白花丹素还能抑制丝裂原诱导的ERK、IKK磷酸化和IκB-α降解。然而，它不影响P38，JNK和AKT的磷酸化。我们的研究结果首次表明，白花丹素的抗增殖作用是通过调节细胞的氧化还原。这些结果为巯基清除剂作为抗炎药物的应用提供了理论基础。
Plumbagin inhibited activation, proliferation, cytokine production, and graft-versus-host disease in lymphocytes and inhibited growth of tumor cells by suppressing nuclear factor-κB (NF-κB). Plumbagin was also shown to induce reactive oxygen species (ROS) generation in tumor cells via an unknown mechanism. Present report describes a novel role of cellular redox in modulation of immune responses in normal lymphocytes by plumbagin. Plumbagin depleted glutathione (GSH) levels that led to increase in ROS generation. The decrease in GSH levels was due to direct reaction of plumbagin with GSH as evinced by mass spectrometric and HPLC analysis. Further, addition of plumbagin to cells resulted in decrease in free thiol groups on proteins and increase in glutathionylation of proteins. The suppression of mitogen-induced T-cell proliferation and cytokine (IL-2/IL-4/IL-6/IFN-γ) production by plumbagin was abrogated by thiol antioxidants but not by non-thiol antioxidants confirming that thiols but not ROS play an important role in biological activity of plumbagin. Plumbagin also abrogated mitogen-induced phosphorylation of ERK, IKK, and degradation of IκB-α. However, it did not affect phosphorylation of P38, JNK, and AKT. Our results for the first time show that antiproliferative effects of plumbagin are mediated by modulation of cellular redox. These results provide a rationale for application of thiol-depleting agents as anti-inflammatory drugs.
登录
查看更多内容
影响因子：
5.6
作者：
Checker, Rahul;Sharma, Deepak;Poduval, T. B.
通讯作者：
Poduval, T. B.
影响因子：
5.8
作者：
Biswas, S;Chida, AS;Rahman, I
通讯作者：
Rahman, I
影响因子：
5.6
作者：
Checker, Rahul;Chatterjee, Suchandra;Poduval, T. B.
通讯作者：
Poduval, T. B.
影响因子：
7.2
作者：
Hazra, B;Sarkar, R;Dinda, B
通讯作者：
Dinda, B
影响因子：
4.4
作者：
Malmberg, KJ;Arulampalam, V;Kiessling, R
通讯作者：
Kiessling, R