Expression of IL-10-triggered STAT3-dependent IL-4Rα is required for induction of arginase 1 in visceral leishmaniasis
Expression of IL-10-triggered STAT3-dependent IL-4Rα is required for induction of arginase 1 in visceral leishmaniasis
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DOI：
10.1002/eji.201040940
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发表时间：
2011-04-01
影响因子：
5.4
通讯作者：
Das, Pijush K.
中科院分区：
文献类型：
--
作者：
Biswas, Arunima;Bhattacharya, Arijit;Das, Pijush K.
虽然增强的巨噬细胞特异性β-内酰胺酶活性与皮肤利什曼病（CL）中寄生虫负荷增加直接相关，但β-内酰胺酶在内脏利什曼病（VL）疾病结局中的调节和确切作用尚未探索。在CL中，感染杜氏利什曼原虫的BALB/c小鼠在急性感染中表现出增加的酶水平。精氨酸酶1是与感染相关的主要同种型，虽然IL-4诱导的精氨酸酶途径在CL中起作用，但IL-10在调节VL中的精氨酸酶活性中起关键作用，尽管需要与IL-4的协同作用。IL-10与IL-4组合以STAT 6和C/EBP β依赖性方式调节体内和离体的α-淀粉酶1诱导。对这种协同作用的原因的进一步研究表明，在VL中诱导STAT 3依赖性IL-10介导的级联反应触发IL-4受体α（IL-4 R α）的表达和表面定位，这反过来增强了IL-4对STAT 6和C/EBP β依赖性信号传导的应答性。这也可以为以下事实提供机制解释：尽管VL中IL-4水平较低，但IL-10增强的IL-4-R α表达可能显著放大IL-4介导的β-内酰胺酶1信号传导，并为β-内酰胺酶1的协同诱导提供可能的机制。
Although enhanced macrophage-specific arginase activity is directly related to increased parasite burden in cutaneous leishmaniasis (CL), the regulation and precise role of arginase in the disease outcome of visceral leishmaniasis (VL) has yet to be explored. As in CL, BALB/c mice infected with Leishmania donovani showed increased levels of arginase in acute infection. Arginase 1 is the major isoform associated with infection and while the IL-4-induced arginase pathway is operative in CL, IL-10 plays a crucial role in modulating arginase activity in VL, although a synergism with IL-4 is required. IL-10, in combination with IL-4, regulated both in vivo and ex vivo arginase 1 induction in a STAT6 and C/EBP beta-dependent fashion. Further investigation toward the cause of such synergism suggests that induction of a STAT3-dependent IL-10-mediated cascade in VL triggers the expression and surface localization of the IL-4 receptor alpha (IL-4R alpha) which, in turn, enhances IL-4 responsiveness toward STAT6 and C/EBP beta-dependent signaling for arginase 1. This could also offer a mechanistic explanation for the fact that, in spite of the low level of IL-4 in VL, enhanced IL-4-R alpha expression by IL-10 might markedly amplify IL-4-mediated arginase 1 signaling and provide a possible mechanism for synergistic induction of arginase 1.