IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis
IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis
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DOI：
10.4049/jimmunol.0802860
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发表时间：
2009-02-15
影响因子：
4.4
通讯作者：
Van Weyenbergh, Johan
中科院分区：
文献类型：
--
作者：
Khouri, Ricardo;Bafica, Andre;Van Weyenbergh, Johan
直到最近，I型干扰素(干扰素-α/β)才在非病毒性传染病中作为免疫调节剂引起了相当大的关注。干扰素-β已被证明以一种非依赖的方式预防由大利什曼原虫引起的旧世界利什曼病，但缺乏关于新世界利什曼病的数据。我们发现，在亚马逊利什曼原虫和感染巴西利什曼原虫的人巨噬细胞中，干扰素-β呈剂量依赖性地增加寄生虫负担，而不依赖于内源性或外源性NO。然而，干扰素-β显著减少了感染利什曼原虫和未感染的人巨噬细胞中超氧化物的释放。在这种超氧化物产生减少的同时，干扰素-β介导的超氧化物歧化酶1(SOD1)蛋白水平显著增加。此外，干扰素-β对利什曼杀菌活性的抑制可被SOD1模拟，并可被药理学或小干扰RNA介导的SOD1抑制所拮抗。最后，在新大陆皮肤利什曼病患者的活检组织中证实了显著的SOD1原位表达。这些发现揭示了利什曼原虫感染中一个迄今未知的干扰素-β/SOD1轴，并提示抑制SOD相关途径可作为治疗亚马逊利什曼原虫和ASL的策略。巴西肺吸虫感染是人类的主要病原体。免疫学杂志，2009,182：2525-2531。
Type I IFNs (IFN-alpha/beta) have only recently gained considerable attention as immunomodulators in nonviral infectious diseases. IFN-beta has been shown to protect, in a NO-dependent manner, against murine Old World leishmaniasis caused by Leishmania major, but data in New World leishmaniasis are lacking. We found that IFN-beta dose-dependently increases parasite burden in Leishmania amazonensis- as well as Leishmania braziliensis-infected human macrophages, independent of endogenous or exogenous NO. However, IFN-beta significantly reduced superoxide release in Leishmania-infected as well as uninfected human macrophages. This decrease in superoxide production was paralleled by a significant IFN-beta-mediated increase in superoxide dismutase 1 (SOD1) protein levels. Additionally, IFN-beta inhibition of leishmanicidal activity was mimicked by SOD1 and antagonized by either pharmacological or small interfering RNA-mediated inhibition of SOD1. Finally, pronounced SOD1 expression in situ was demonstrated in biopsies from New World cutaneous leishmaniasis patients. These findings reveal a hitherto unknown IFN-beta/SOD1 axis in Leishmania infection and suggest that inhibition of SOD-associated pathways could serve as strategy in the treatment of L. amazonensis as well asL. braziliensis infection, major human pathogens. The Journal of Immunology, 2009,182: 2525-2531.