Calandra Thierry
Division of infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Scand J Infect Dis. 2003;35(9):573-6. doi: 10.1080/00365540310016277.
Among innate immune cells, macrophages play an essential role in the sensing and elimination of invasive microorganisms. Binding of microbial products to pathogen-recognition receptors stimulates macrophages to release cytokines and other effector molecules that orchestrate the host innate and adaptive immune responses. Recently, the protein known as macrophage migration inhibitory factor (MIF) has emerged as a pivotal mediator of innate immunity. First identified as a T-cell cytokine, MIF was rediscovered as a protein released by pituitary cells after exposure to endotoxin [lipopolysaccharide (LPS)] or bacteria and in response to stress. Monocytes, macrophages and lymphocytes constitutively express MIF, which is rapidly released after stimulation with bacterial endotoxins and exotoxins, and cytokines. MIF induces powerful proinflammatory biological responses and has been shown to be an important effector molecule of septic shock. High levels of MIF have been detected in the circulation of patients with severe sepsis and septic shock. Inhibition of MIF activity with neutralizing anti-MIF antibodies or deletion of the Mif gene led to a marked reduction in cytokine production and protected mice from lethal bacterial sepsis and toxic shock induced by Gram-negative endotoxin or Gram-positive exotoxins. Investigations into the mechanisms whereby MIF modulates innate immune responses to endotoxin and Gram-negative bacteria have shown that MIF up-regulates the expression of Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex. Thus, MIF enables cells, such as the macrophage, that are at the forefront of the host antimicrobial defences, to sense promptly the presence of invading Gram-negative bacteria and mount an innate immune response. Given that it is a pivotal regulator of innate immune responses to bacterial infections, MIF appears to be a perfect target for novel therapeutic interventions in patients with severe sepsis.
在天然免疫细胞中，巨噬细胞在感知和清除入侵微生物方面发挥着重要作用。微生物产物与病原体识别受体的结合刺激巨噬细胞释放细胞因子和其他效应分子，从而协调宿主的天然免疫和适应性免疫反应。最近，一种名为巨噬细胞移动抑制因子（MIF）的蛋白质已成为天然免疫的关键介质。MIF最初被鉴定为一种T细胞细胞因子，后来在内毒素[脂多糖（LPS）]或细菌刺激后以及对应激作出反应时，被重新发现为垂体细胞释放的一种蛋白质。单核细胞、巨噬细胞和淋巴细胞组成性表达MIF，在用细菌内毒素、外毒素和细胞因子刺激后，MIF会迅速释放。MIF可诱导强烈的促炎生物学反应，并且已被证明是脓毒性休克的重要效应分子。在严重脓毒症和脓毒性休克患者的循环系统中检测到高水平的MIF。用中和性抗MIF抗体抑制MIF活性或删除Mif基因，可导致细胞因子产生显著减少，并保护小鼠免受革兰氏阴性内毒素或革兰氏阳性外毒素引起的致命细菌性脓毒症和中毒性休克。对MIF调节对内毒素和革兰氏阴性菌天然免疫反应机制的研究表明，MIF上调Toll样受体4（TLR4）的表达，TLR4是LPS受体复合物的信号转导分子。因此，MIF使处于宿主抗菌防御前沿的细胞，如巨噬细胞，能够迅速感知入侵革兰氏阴性菌的存在并引发天然免疫反应。鉴于MIF是细菌感染天然免疫反应的关键调节因子，它似乎是严重脓毒症患者新型治疗干预的理想靶点。
