MIF regulates innate immune responses through modulation of Toll-like receptor 4
MIF regulates innate immune responses through modulation of Toll-like receptor 4
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DOI：
10.1038/414920a
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发表时间：
2001-12-20
期刊：
影响因子：
64.8
通讯作者：
Calandra, T
中科院分区：
文献类型：
--
作者：
Roger, T;David, J;Calandra, T
巨噬细胞是天然免疫系统的关键效应细胞，对于识别和清除入侵的微生物病原体至关重要（1,2）。当微生物产物与病原体识别受体结合时，巨噬细胞被激活并释放多种细胞因子（3），这些细胞因子协调宿主的天然免疫和适应性免疫应答。巨噬细胞移动抑制因子（MIF）最初被鉴定为一种T细胞细胞因子（4,5），它也是一种巨噬细胞细胞因子，是炎症和败血症的重要介质（6 - 12）。在此我们报道，MIF是巨噬细胞对内毒素（脂多糖）和革兰氏阴性菌应答的关键调节因子。与野生型细胞相比，MIF缺陷型巨噬细胞对脂多糖和革兰氏阴性菌反应低下，表现为核因子-κB活性以及肿瘤坏死因子-α产生显著降低。这种降低是由于脂多糖受体复合物的信号转导分子Toll样受体4（TLR4）的下调，并且与转录因子PU.1活性降低有关，而PU.1是髓系细胞中Tlr4基因最佳表达所必需的。这些发现确定了MIF在天然免疫中的重要作用，并为MIF缺陷小鼠对内毒素休克的抵抗提供了分子基础。
Macrophages are pivotal effector cells of the innate immune system, which is vital for recognizing and eliminating invasive microbial pathogens(1,2). When microbial products bind to pathogen-recognition receptors, macrophages become activated and release a broad array of cytokines(3) that orchestrate the host innate and adaptive immune responses. Initially identified as a T-cell cytokine(4,5), macrophage migration inhibitory factor (MIF) is also a macrophage cytokine and an important mediator of inflammation and sepsis(6-12). Here we report that MIF is an essential regulator of macrophage responses to endotoxin (lipopolysaccharide) and Gram-negative bacteria. Compared with wild-type cells, MIF-deficient macrophages are hyporesponsive to lipopolysaccharide and Gram-negative bacteria, as shown by a profound reduction in the activity of NF-kappaB and the production of tumour-necrosis factor-alpha. This reduction is due to a downregulation of Toll-like receptor 4 (TLR4), the signal-transducing molecule of the lipopolysaccharide receptor complex, and is associated with decreased activity of transcription factor PU.1, which is required for optimal expression of the Tlr4 gene in myeloid cells. These findings identify an important role for MIF in innate immunity and provide a molecular basis for the resistance of MIF-dercient mice to endotoxic shock.