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MIF and the Genetic Basis of Macrophage Responsiveness

机译：MIF和巨噬细胞反应性的遗传基础

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Macrophage migration inhibitory factor (MIF) describes one of the first cytokine activities to be discovered, but the precise role of this immunologic mediator in the host response only now is being understood. MIF is produced constitutively by diverse cell types, and it circulates normally in the blood at low but immunoregulatory concentrations. Diverse pro-inflammatory or invasive stimuli lead to a rapid upregulation in the release of MIF from pre-formed stores in monocytes/macrophages and other cell types. MIF is necessary for the optimal production of TNF and IL-1, and it upregulates the expression of innate receptors such as TLR-4 and a number of secondary effectors important for innate immunity. Once secreted, MIF has a unique role in inhibiting the activation-induced, p53-dependent apoptosis of monocytes/ macrophages, which is a response that serves to spatially and temporally limit monocyte/macrophage activation responses. This action of MIF results in a necessary but, in certain circumstances, pathologically excessive proinflammatory response. MIF also induces a sustained pattern of ERK-1/2 MAP kinase activation, and it regulates Jab1- mediated transcriptional pathways. Recent studies have identified functional, promoter polymorphisms in the human MIF gene that control its level of expression and that now are being associated with the incidence or the severity of different inflammatory diseases. The different promoter-based MIF alleles appear to exist in a balanced polymorphism that may broadly control innate responsiveness in the human population. These alleles also show significant population stratification, suggesting that the MIF locus may have been subject to different selective pressure over time. The evolutionary persistence of functionally distinct MIF alleles may ensure an essential degree of variation in innate responsiveness for human immunity.
机译：巨噬细胞迁移抑制因子（MIF）描述了第一个被发现的细胞因子活性，但是这种免疫介质在宿主反应中的确切作用目前尚不清楚。 MIF由多种细胞类型组成性地产生，并且在血液中以低但免疫调节的浓度正常循环。不同的促炎性或侵入性刺激导致单核细胞/巨噬细胞和其他细胞类型中预先形成的存储中MIF释放的快速上调。 MIF对于最佳产生TNF和IL-1是必需的，它会上调先天受体（例如TLR-4）的表达以及许多对于先天免疫至关重要的次级效应子。一旦被分泌，MIF在抑制活化诱导的单核细胞/巨噬细胞的依赖于p53的凋亡中具有独特的作用，这是一种在空间和时间上限制单核细胞/巨噬细胞活化反应的反应。 MIF的这种作用会导致必要的（但在某些情况下）病理上过度的促炎反应。 MIF还诱导ERK-1 / 2 MAP激酶激活的持续模式，并调节Jab1介导的转录途径。最近的研究已经确定了人类MIF基因中的功能性启动子多态性，可以控制其表达水平，并且目前与各种炎症性疾病的发生率或严重程度有关。不同的基于启动子的MIF等位基因似乎以平衡的多态性存在，可以广泛控制人类的先天反应。这些等位基因还显示出显着的群体分层，表明随着时间的流逝，MIF基因座可能受到不同的选择压力。功能上不同的MIF等位基因的进化持久性可以确保人类免疫的先天反应性达到必要的变化程度。

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