MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by Leishmania mexicana
MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by Leishmania mexicana
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DOI：
10.1371/journal.ppat.1001192
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发表时间：
2010-11-01
期刊：
影响因子：
6.7
通讯作者：
Plevin, Robin
中科院分区：
文献类型：
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作者：
Al-Mutairi, Mashael S.;Cadalbert, Laurence C.;Plevin, Robin
在这项研究中，我们使用靶向缺失策略构建了一种新型的双特异性磷酸酶4(DUSP4)缺失小鼠，以检测MKP-2在免疫反应中的作用。脂多糖(LPS)诱导MKP-2(+/+)小鼠骨髓来源的巨噬细胞MKP-2蛋白表达迅速增加，且呈时间和浓度依赖性，而MKP-2(-/-)小鼠的MKP-2蛋白表达无明显变化。脂多糖诱导的MKP-2(-/-)巨噬细胞JNK和p38 MAP激酶的磷酸化显著增加并延长，而ERK的磷酸化不受影响。MKP-2缺失也增强了内毒素诱导的炎性细胞因子IL-6、IL-12p40、TNF-α和COX-2衍生的PGE(2)的产生。然而，令人惊讶的是，在MKP-2(-/-)巨噬细胞中，内毒素或干扰素-γ诱导的iNOS和NO释放明显减少，精氨酸酶-1的基础表达增强，提示MKP-2在病原体介导的免疫中可能具有额外的调节功能。事实上，在感染细胞内寄生虫墨西哥利什曼原虫后，与野生型小鼠相比，MKP-2(-/-)小鼠显示出更大的病变大小和寄生虫负担，并显著修改了Th1/Th2偏向。然而，通过抗CD3诱导的干扰素-γ的产生来检测MKP-2(-/-)T细胞的功能并没有固有的缺陷。相反，MKP-2(-/-)骨髓来源的巨噬细胞被发现天生更容易感染墨西哥利什曼原虫，这一效果在精氨酸酶抑制剂NOR-NOHA治疗后被逆转。这些发现首次显示了MKP-2在体内的作用，并表明MKP-2可能在巨噬细胞水平上协调对细胞内感染的保护作用。
In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2(+/+) but not from MKP-2(-/-) mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2(-/-) macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-alpha, and also COX-2 derived PGE(2) production. However surprisingly, in MKP-2(-/-) macrophages, there was a marked reduction in LPS or IFN gamma-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2(-/-) mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2(-/-) T cell function as measured by anti-CD3 induced IFN-gamma production. Rather, MKP-2(-/-) bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage.