Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages
Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages
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DOI：
10.1042/bj20061430
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发表时间：
2007-03-01
影响因子：
4.1
通讯作者：
Cassard-Doulcier, Anne-Marie
中科院分区：
文献类型：
--
作者：
Emre, Yalin;Hurtaud, Corinne;Cassard-Doulcier, Anne-Marie
线粒体是能量代谢的主要细胞器，也是产生活性氧的主要场所。脂多糖（LPS）诱导的活性氧信号传导是巨噬细胞激活中的关键事件。在本文中，我们报告的部分LPS介导的ROS信号来自线粒体内的信号放大环，增强MAPK（丝裂原活化蛋白激酶）激活。更确切地说，我们已经确定了线粒体内膜UCP 2（解偶联蛋白2）作为ROS信号传导的生理制动器。LPS刺激小鼠骨髓来源的巨噬细胞通过JNK（c-Jun N-末端激酶）和p38途径快速下调UCP 2。UCP 2的下调被证明是必要的，以增加线粒体ROS的生产，以加强MAPK的激活。与此一致，UCP 2缺陷型巨噬细胞表现出增强的炎症状态，其特征在于一氧化氮产生增加和迁移能力提高。此外，我们发现UCP 2的缺乏使巨噬细胞对一氧化氮诱导的细胞凋亡更具抵抗力。
The mitochondrion is a major organelle contributing to energy metabolism but also a main site of ROS (reactive oxygen species) production. LPS (lipopolysaccharide)-induced ROS signalling is a critical event in macrophage activation. In the present paper we report that part of LPS-mediated ROS signalling comes from mitochondria inside a signal amplification loop that enhances MAPK (mitogen-activated protein kinase) activation. More precisely, we have identified the inner mitochondrial membrane UCP2 (uncoupling protein 2) as a physiological brake on ROS signalling. Stimulation of murine bone marrow-derived macrophages by LPS quickly down-regulated UCP2 through the JNK (c-Jun N-terminal kinase) and p38 pathways. UCP2 down-regulation was shown to be necessary to increase mitochondrial ROS production in order to potentiate MAPK activation. Consistent with this, UCP2-deficient macrophages exhibit an enhanced inflammatory state characterized by increased nitric oxide production and elevated migration ability. Additionally, we found that the absence of UCP2 renders macrophages more resistant to nitric oxide-induced apoptosis.