A Leishmania ortholog of macrophage migration inhibitory factor modulates host macrophage responses
A Leishmania ortholog of macrophage migration inhibitory factor modulates host macrophage responses
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DOI：
10.4049/jimmunol.180.12.8250
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发表时间：
2008-06-15
影响因子：
4.4
通讯作者：
Bucala, Richard
中科院分区：
文献类型：
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作者：
Kamir, Daniela;Zierow, Swen;Bucala, Richard
寄生生物已经进化出专门的策略来逃避免疫防御机制。我们在这里描述了一种细胞因子的同源基因，巨噬细胞移动抑制因子(MIF)，它是由专性细胞内寄生虫大利什曼原虫产生的。利什曼原虫MIF蛋白Lm1740MIF的高分辨率X射线晶体结构(1.03埃)表明，它与人MIF具有显著的结构同源性。N端互变异构化位点的两种蛋白质之间的差异是明显的，我们提供了针对该位点的小分子拮抗剂选择性、物种特异性地抑制MIF的证据。Lm1740MIF与MIF受体CD74有显著的结合作用(K-d=2.9×10(-8)M)。与哺乳动物类似，Lm1740MIF以CD74依赖的方式诱导ERK1/2 MAPK激活，并抑制激活诱导的巨噬细胞凋亡。Lm1740MIF抑制细胞凋亡的能力可能有助于利什曼原虫在巨噬细胞内的持续存在，并有助于其逃避免疫破坏。
Parasitic organisms have evolved specialized strategies to evade immune defense mechanisms. We describe herein an ortholog of the cytokine, macrophage migration inhibitory factor (MIF), which is produced by the obligate intracellular parasite, Leishmania major. The Leishmania MIF protein, Lm1740MIF, shows significant structural homology with human MIF as revealed by a high-resolution x-ray crystal structure (1.03 angstrom). Differences between the two proteins in the N-terminal tautomerization site are evident, and we provide evidence for the selective, species-specific inhibition of MIF by small-molecule antagonists that target this site. Lm1740MIF shows significant binding interaction with the MIF receptor, CD74 (K-d = 2.9 x 10(-8) M). Like its mammalian counterpart, Lm1740MIF induces ERK1/2 MAP kinase activation in a CD74-dependent manner and inhibits the activation-induced apoptosis of macrophages. The ability of Lm1740MIF to inhibit apoptosis may facilitate the persistence of Leishmania within the macrophage and contribute to its evasion from immune destruction.