Mitochondrial Ca²⁺ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function.
Mitochondrial Ca²⁺ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function.
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DOI：
10.7554/elife.06376
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发表时间：
2015-05-14
期刊：
影响因子：
7.7
通讯作者：
Rincón M
中科院分区：
文献类型：
--
作者：
Yang R;Lirussi D;Thornton TM;Jelley-Gibbs DM;Diehl SA;Case LK;Madesh M;Taatjes DJ;Teuscher C;Haynes L;Rincón M
IL-6在决定效应CD4细胞和这些细胞产生的细胞因子的命运中起着重要作用。在这里，我们确定了IL-6调节CD4细胞效应功能的一种新的分子机制。我们发现il -6依赖的信号促进了线粒体呼吸链超复合体的形成，以维持CD4细胞激活后期的高线粒体膜电位。由IL-6引起的线粒体超极化通过氧化磷酸化与ATP的产生分离。然而，这是在CD4细胞激活后期提高线粒体Ca2+水平的一种机制。在IL-6存在的情况下，线粒体Ca2+水平的增加用于延长效应CD4细胞中il - 4和il - 21的表达。因此，IL-6对线粒体膜电位和线粒体Ca2+的影响是IL-6调节CD4细胞效应功能的另一途径，可能参与炎症性疾病的发病机制。DOI: http://dx.doi.org/10.7554/eLife.06376.001炎症是身体对感染或损伤的正常反应，它有助于开始愈合过程。然而，如果不加以控制，炎症本身就会损害组织，而类风湿关节炎等疾病就是炎症不受控制的结果。某些免疫细胞释放的分子可以触发或抑制炎症。白细胞介素6是“促炎”分子的一个例子，它调节被统称为“CD4细胞”的免疫细胞群的活动。超重或肥胖的人比体重正常的人有更高的白细胞介素6水平。肥胖和其他代谢疾病与线粒体结构的问题有关，线粒体产生一种叫做三磷酸腺苷的分子，为细胞提供生存所需的能量。但目前尚不清楚白细胞介素6是否会影响CD4细胞内线粒体的活性。现在，Yang等人发现白细胞介素6可以影响CD4细胞内的线粒体，并在此过程中发现了白细胞介素6调节这些细胞活性的新途径。涉及小鼠免疫细胞的实验表明，白细胞介素6触发一系列信号事件，有助于在CD4细胞中形成所谓的“线粒体呼吸链超复合体”。这些是在线粒体膜中一起工作的蛋白质组，对这些结构的活性至关重要。这些超复合体的形成维持了在CD4细胞激活后期发生的线粒体膜上的大电压差。Yang等人发现这种电压差异与ATP的产生无关，但它确实提高了线粒体内钙离子的水平。进一步的实验表明，这些钙离子水平的增加延长了CD4细胞中其他促炎分子的产生。在发现了调节CD4细胞活性的新途径之后，下一个挑战是看看这一途径的部分是否可以被药物靶向，以帮助治疗炎症性疾病，如风湿性关节炎。此外，由于白细胞介素6在癌症等其他疾病中发挥着积极作用，对这一新途径的进一步研究可能有助于解释这种分子如何促进癌症在体内的进展和/或扩散。DOI: http://dx.doi.org/10.7554/eLife.06376.002
IL-6 plays an important role in determining the fate of effector CD4 cells and the cytokines that these cells produce. Here we identify a novel molecular mechanism by which IL-6 regulates CD4 cell effector function. We show that IL-6-dependent signal facilitates the formation of mitochondrial respiratory chain supercomplexes to sustain high mitochondrial membrane potential late during activation of CD4 cells. Mitochondrial hyperpolarization caused by IL-6 is uncoupled from the production of ATP by oxidative phosphorylation. However, it is a mechanism to raise the levels of mitochondrial Ca2+ late during activation of CD4 cells. Increased levels of mitochondrial Ca2+ in the presence of IL-6 are used to prolong Il4 and Il21 expression in effector CD4 cells. Thus, the effect of IL-6 on mitochondrial membrane potential and mitochondrial Ca2+ is an alternative pathway by which IL-6 regulates effector function of CD4 cells and it could contribute to the pathogenesis of inflammatory diseases. DOI: http://dx.doi.org/10.7554/eLife.06376.001 Inflammation is a normal part of the body's response to an infection or injury and it helps to start the healing process. However, if left unchecked, inflammation itself can damage tissues, and diseases such as rheumatoid arthritis are the result of uncontrolled inflammation. Certain immune cells release molecules that can either trigger or suppress inflammation. Interleukin 6 is an example of a ‘pro-inflammatory’ molecule, which regulates the activity of groups of immune cells collectively known as ‘CD4 cells’. People who are overweight or obese have higher levels of interleukin 6 than people of a healthy weight. Obesity and other metabolic conditions have been linked to problems with structures called mitochondria, which make a molecule called ATP that provides cells with the energy they need to survive. But it is not known if interleukin 6 can affect the activity of mitochondria inside CD4 cells. Now, Yang et al. have discovered that interleukin 6 can affect the mitochondria inside CD4 cells and, in doing so, have identified a new way that interleukin 6 can regulate these cells' activity. Experiments involving immune cells from mice revealed that interleukin 6 triggers a cascade of signaling events that aid the formation of so-called ‘mitochondrial respiratory chain supercomplexes’ in CD4 cells. These are groups of proteins that work together in the membranes of mitochondria and are vital for the activity of these structures. The formation of these supercomplexes maintains a large voltage difference across the membrane of the mitochondria that occurs during the later stages of CD4 cell activation. Yang et al. found that this voltage difference was not linked to the production of ATP, but that it did raise the levels of calcium ions inside the mitochondria. Further experiments revealed that these increased levels of calcium ions prolong the production of other pro-inflammatory molecules in the CD4 cells. Following the discovery of a new pathway that regulates the activity of CD4 cells, the next challenge is to see if the parts of this pathway could be targeted with drugs to help treat inflammatory diseases such as rheumatoid arthritis. Moreover, because interleukin 6 plays an active role in other diseases such as cancer, further studies of this new pathway may help explain how this molecule encourages cancers to progress and/or spread around the body. DOI: http://dx.doi.org/10.7554/eLife.06376.002