Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages
Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages
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DOI：
10.4049/jimmunol.169.11.6408
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发表时间：
2002-12-01
影响因子：
4.4
通讯作者：
Liu, YS
中科院分区：
文献类型：
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作者：
Chen, PL;Li, J;Liu, YS
巨噬细胞暴露于LPS会通过复杂的信号传导机制产生促炎细胞因子，如tnf - α。丝裂原活化蛋白（MAP）激酶在这一过程中起着关键作用。在本研究中，我们利用RAW264.7巨噬细胞研究了MAP激酶磷酸酶-1 （MKP-1）在调节促炎细胞因子产生中的作用。MAP激酶活性分析显示，LPS刺激后c-Jun n -末端激酶（JNK）和p38瞬间活化。有趣的是，MKP-1在JNK和p38失活的同时被诱导，而雷公藤甲素阻断MKP-1的诱导可以阻止这种失活。MKP-1的异位表达加速了JNK和p38的失活，并显著抑制了tnf - α和IL-6的产生。发现LPS诱导MKP-1依赖于细胞外信号调节的激酶，并涉及基因表达增强和蛋白质稳定性增加。最后，在动物模型中，糖皮质激素和霍乱毒素B亚基（一种能够预防自身免疫性疾病的药物）也能诱导MKP-1表达。这些发现强调了MKP-1作为巨噬细胞炎症反应的关键负调节因子，强调了其作为开发新型抗炎药物的潜在靶点的前提。
Exposure of macrophages to LPS elicits the production of proinflammatory cytokines, such as TNF-alpha, through complex signaling mechanisms. Mitogen-activated protein (MAP) kinases play a critical role in this process. In the present study, we have addressed the role of MAP kinase phosphatase-1 (MKP-1) in regulating proinflammatory cytokine production using RAW264.7 macrophages. Analysis of MAP kinase activity revealed a transient activation of c-Jun N-terminal kinase (JNK) and p38 after LPS stimulation. Interestingly, MKP-1 was induced concurrently with the inactivation of JNK and p38, whereas blocking MKP-1 induction by triptolide prevented this inactivation. Ectopic expression of MKP-1 accelerated JNK and p38 inactivation and substantially inhibited the production of TNF-alpha and IL-6. Induction of MKP-1 by LPS was found to be extracellular signal-regulated kinase dependent and involved enhanced gene expression and increased protein stability. Finally, MKP-1 expression was also induced by glucocorticoids as well as cholera toxin B subunit, an agent capable of preventing autoimmune diseases in animal models. These findings highlight MKP-1 as a critical negative regulator of the macrophage inflammatory response, underscoring its premise as a potential target for developing novel anti-inflammatory drugs.