Phagocytosis of hemozoin enhances matrix metalloproteinase-9 activity and TNF-α production in human monocytes:: Role of matrix metalloproteinases in the pathogenesis of falciparum malarial
Phagocytosis of hemozoin enhances matrix metalloproteinase-9 activity and TNF-α production in human monocytes:: Role of matrix metalloproteinases in the pathogenesis of falciparum malarial
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DOI：
10.4049/jimmunol.175.10.6436
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发表时间：
2005-11-15
影响因子：
4.4
通讯作者：
Arese, P
中科院分区：
文献类型：
--
作者：
Prato, M;Giribaldi, G;Arese, P
基质金属蛋白酶-9 (MMP-9) 由活化的单核细胞分泌，可降解基质蛋白、破坏基底层并激活其前体中的 TNF-α。反过来，TNF-α 增强单核细胞中 MMP-9 的合成。我们在此表明，滋养体寄生的红细胞/疟原虫喂养的贴壁人单核细胞表现出增加的 MMP-9 活性和蛋白质/mRNA 表达，产生时间依赖性的 TNF-α，并表现出更高的基质侵袭能力。 MMP-9 激活对滋养体/疟原虫色素喂养的单核细胞具有特异性，依赖于 TNF-α 的产生，并被抗 TNF-α Ab 和 MMP-9/MMP-13 活性的特异性抑制剂所消除。疟原虫色素诱导的 MMP-9 和 TNF-α 产生的增强会产生双重效应：启动并供给循环强化循环，其中疟原虫色素增强 TNF-α 的产生，进而诱导 MMP-9 的激活和 TNF-α 脱落到细胞外区室；其次，破坏内皮细胞的基底层。 TNF-α 的过量产生和基底层的破坏以及血细胞外渗到血管周围组织是严重疟疾的标志。 MMP-9 的药理学抑制可能为控制疟疾的致病机制提供新的机会。
Matrix metalloproteinase-9 (MMP-9), secreted by activated monocytes, degrades matrix proteins, disrupts basal lamina, and activates TNF-alpha from its precursors. In turn, TNF-alpha enhances synthesis of MMP-9 in monocytes. We show here that trophozoite-parasitized RBCs/hemozoin-fed adherent human monocytes displayed increased MMP-9 activity and protein/mRNA expression, produced TNF-alpha time-dependently, and showed higher matrix invasion ability. MMP-9 activation was specific for trophozoite/ hemozoin-fed monocytes, was dependent on TNF-alpha production, and abrogated by anti-TNF-alpha Ab and by a specific inhibitor of MMP-9/MMP-13 activity. Hemozoin-induced enhancement of MMP-9 and TNF-a production would have a 2-fold effect: to start and feed a cyclic reinforcement loop in which hemozoin enhances production of TNF-alpha, which in turn induces both activation of MMP-9 and shedding of TNF-alpha into the extracellular compartment; and, second, to disrupt the basal lamina of endothelia. Excess production of TNF-alpha and disruption of the basal lamina with extravasation of blood cells into perivascular tissues are hallmarks of severe malaria. Pharmacological inhibition of MMP-9 may offer a new chance to control pathogenic mechanisms in malaria.