Signaling abnormalities in systemic lupus erythematosus as potential drug targets.
Signaling abnormalities in systemic lupus erythematosus as potential drug targets.
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DOI：
10.2174/187153006779025748
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发表时间：
2006-11
期刊：
影响因子：
--
通讯作者：
D. Fernandez;E. Bonilla;P. Phillips;A. Perl
中科院分区：
文献类型：
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作者：
D. Fernandez;E. Bonilla;P. Phillips;A. Perl
系统性红斑狼疮（SLE）是一种自身免疫性炎症性疾病，其特征是T细胞、B细胞和树突状细胞功能障碍和抗核自身抗体产生。近年来，关于SLE的许多知识都与疾病中存在的分子信号异常有关。在SLE中，通过T细胞受体（TCR）的信号传导受到许多蛋白激酶的定位、数量和活性的改变的影响。TCR刺激从细胞内储存释放钙，这触发细胞外钙的流入并激活许多基因的转录，包括白细胞介素-2。SLE患者的短期钙流动被夸大，但长期钙流动减少，可能是次优白细胞介素-2产生的原因。SLE T细胞具有与增加的线粒体质量、高水平的活性氧（ROS）和低水平的ATP相关的持续超极化的线粒体，这减少了活化诱导的细胞凋亡，而是使T细胞易于坏死，从而刺激SLE中的炎症。戊糖磷酸途径影响线粒体电位，并代表可能的干预目标。一氧化氮（NO）是一个潜在的联系，以联系在一起的信号和线粒体异常在SLE。NO诱导的线粒体生物发生再现了SLE T细胞的TCR刺激的钙流动异常。由于线粒体可以储存钙，线粒体质量的增加可能与SLE T细胞中的异常钙流动有关。雷帕霉素的哺乳动物靶点感知线粒体电位并调节钙释放，作为治疗SLE的新靶点。
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by T-cell, B-cell, and dendritic cell dysfunction and antinuclear autoantibody production. Much of the knowledge that has been gained about SLE in recent years is related to molecular signaling abnormalities present in the disease. Signaling through the T-cell receptor (TCR) is affected in SLE by alterations in the localization, amount, and activity of numerous protein kinases. TCR stimulation releases calcium from intracellular stores, which triggers an influx of extracellular calcium and activates the transcription of many genes, including interleukin-2. Short-term calcium fluxing is exaggerated in SLE, but long-term calcium fluxing is diminished and may account for sub-optimal interleukin-2 production. SLE T-cells have persistently hyperpolarized mitochondria associated with increased mitochondrial mass, high levels of reactive oxygen species (ROS) and low levels of ATP, which decrease activation-induced apoptosis and instead predispose T cells for necrosis, thus stimulating inflammation in SLE. The pentose phosphate pathway impacts the mitochondrial potential and represents a target for possible intervention. Nitric oxide (NO) is a potential link to tie together the signaling and mitochondrial abnormalities in SLE. NO-induced mitochondrial biogenesis recapitulates the TCR-stimulated calcium fluxing abnormalities of SLE T-cells. Since mitochondria can store calcium, the increase in mitochondrial mass may be implicated in the aberrant calcium fluxing in SLE T cells. The mammalian target of rapamycin senses the mitochondrial potential and regulates calcium release, serving as a novel target of treatment of SLE.