Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1
Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1
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DOI：
10.1038/ni1310
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发表时间：
2006-03-01
影响因子：
30.5
通讯作者：
Mackay, CR
中科院分区：
文献类型：
--
作者：
Jeffrey, KL;Brummer, T;Mackay, CR
有丝分裂原活化蛋白激酶促进许多细胞过程，对免疫细胞功能至关重要。它们的活性受激酶和双特异性磷酸酶控制。对人类白细胞进行的全面微阵列分析发现，DUSP2（编码磷酸酶PAC-1）是激活免疫细胞中最容易诱导的转录物之一。我们产生了Dusp2（-/-）小鼠，并发现在类风湿关节炎的“K/BxN”模型中炎症反应显著降低。PAC-1缺乏导致Jun激酶（Jnk）活性增加，但细胞外信号调节激酶（Erk）和激酶p38活性意外受损，转录因子Elk1和动员转录因子NFAT和AP-1转录因子复合物活性降低，效应免疫细胞功能下降。因此，PAC-1是炎症细胞信号传导和效应功能的关键正调节因子，通过Jnk和Erk有丝分裂原激活的蛋白激酶串扰介导。
Mitogen-activated protein kinases facilitate many cellular processes and are essential for immune cell function. Their activity is controlled by kinases and dual-specificity phosphatases. A comprehensive microarray analysis of human leukocytes identified DUSP2 ( encoding the phosphatase PAC-1) as one of the most highly induced transcripts in activated immune cells. We generated Dusp2(-/-) mice and found considerably reduced inflammatory responses in the 'K/BxN' model of rheumatoid arthritis. PAC-1 deficiency led to increased activity of Jun kinase (Jnk) but unexpected impairment of the activity of extracellular signal-regulated kinase (Erk) and the kinase p38, reduced activity of the transcription factor Elk1 and a complex of mobilized transcription factor NFAT and the AP-1 transcription factor and decreased effector immune cell function. Thus, PAC-1 is a key positive regulator of inflammatory cell signaling and effector functions, mediated through Jnk and Erk mitogen-activated protein kinase crosstalk.