Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages
Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages
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DOI：
10.4049/jimmunol.178.2.1077
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发表时间：
2007-01-15
影响因子：
4.4
通讯作者：
Zhang, Xia
中科院分区：
文献类型：
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作者：
Yang, Ziyan;Mosser, David M.;Zhang, Xia
IL-10是决定宿主对利什曼原虫易感性的关键细胞因子。我们先前证明巨噬细胞来源的IL-10可能导致疾病恶化，但利什曼原虫感染导致IL-10诱导的机制尚不完全清楚。在这项研究中，我们证明了感染亚马逊利什曼原虫的巨噬细胞可以激活MAPK，ERK1/2。这种激活是诱导IL-10所必需的，但不是充分的。除ERK激活外，还有一种炎性刺激，如低分子量。细胞外基质中的透明质酸也必须存在。这两种信号的结合导致了IL-10的超诱导。我们还证明，利什曼原虫无鞭毛体表面的免疫球蛋白需要从感染的巨噬细胞中产生最大的IL-10。表面免疫球蛋白与巨噬细胞Fc-γR结合，诱导ERK活化。缺乏Fc-Gamma R的巨噬细胞，或经脾酪氨酸激酶抑制剂处理的巨噬细胞，在感染利什曼原虫后，未能激活ERK，因此无法产生IL-10。我们证实ERK1/2的激活导致了组蛋白H3在IL-10启动子上的磷酸化，这种磷酸化允许转录因子Sp1与IL-10启动子结合。最后，给受感染的小鼠服用ERK激活的抑制剂U0126，可以减缓病变进展，减少体内寄生虫的数量。因此，我们的发现揭示了MAPK、ERK信号在利什曼原虫感染发病机制中的重要作用。
IL-10 is a critical cytokine in determining host susceptibility to Leishmania spp. We previously demonstrated that macrophagederived IL-10 could contribute to disease exacerbation, but the mechanisms whereby Leishmania infections led to IL-10 induction were not fully understood. In this study, we demonstrated that infection of macrophages with Leishmania amazonensis amastigotes led to the activation of the MAPK, ERK1/2. This activation was required, but not sufficient for IL-10 induction. In addition to ERK activation, an inflammatory stimulus, such as low m.w. hyaluronic acid from the extracellular matrix, must also be present. The combination of these two signals resulted in the superinduction of IL-10. We also demonstrated that IgG on the surface of Leishmania amastigotes was required to achieve maximal IL-10 production from infected macrophages. Surface IgG engages macrophage Fc gamma R to induce ERK activation. Macrophages lacking Fc gamma R, or macrophages treated with an inhibitor of spleen tyrosine kinase, the tyrosine kinase that signals via Fc gamma R, failed to activate ERK and consequently failed to produce IL-10 following infection with Leishmania amastigotes. We confirmed that ERK1/2 activation led to the phosphorylation of histone H3 at the IL-10 promoter, and this phosphorylation allowed for the binding of the transcription factor, Sp1, to the IL-10 promoter. Finally, the administration of U0126, an inhibitor of ERK activation, to infected mice resulted in decreased lesion progression with reduced numbers of parasites in them. Thus, our findings reveal an important role of MAPK, ERK signaling in the pathogenesis of Leishmania infection.