Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of gram-positive bacteria
Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of gram-positive bacteria
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DOI：
10.1073/pnas.95.19.11383
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发表时间：
1998-09-15
影响因子：
11.1
通讯作者：
Bucala, R
中科院分区：
文献类型：
--
作者：
Calandra, T;Spiegel, LA;Bucala, R
在20世纪60年代早期作为T细胞细胞因子被发现，被称为巨噬细胞迁移抑制因子（MIF）的蛋白质介体最近被发现是在生理应激反应期间释放的垂体肽、在LPS刺激后分泌的促炎巨噬细胞因子和作为抗原依赖性活化反应的一部分表达的T细胞产物。在RAW 264.7或激发的小鼠腹腔巨噬细胞中，低至10 pg/ml的葡萄球菌中毒性休克综合征（TSS）毒素1（TSST-1）和链球菌致热性外毒素A（A）均可诱导MIF分泌达到峰值。脾细胞细胞因子产生的剂量反应研究表明，较低浓度的TSST-1（10 pg/ml）比诱导白细胞介素2或干扰素-γ分泌（1 ng/ml）更需要释放MIF，我们还研究了中和性抗MIF抗体对TSST-1诱导的淋巴细胞增殖和致死性中毒性休克的影响。在TSST-1注射前2小时用抗-MIF抗体预处理C57 BL/6小鼠防止了脾增大，并使离体测量的脾细胞增殖减少了50%。In.在TSST-1诱导的休克致死小鼠模型中，抗MIF抗体使存活率从8%增加到54%（P < 0.0001）。这些研究表明，革兰氏阳性外毒素是MIF分泌的极其有效的诱导剂，并确立了MIF和巨噬细胞在TSS发病机制和先天免疫应答中的关键作用。
Discovered in the early 1960s as a T cell cytokine, the protein mediator known as macrophage migration inhibitory factor (MIF) has been found recently to be a pituitary peptide released during the physiological stress response, a proinflammatory macrophage cytokine secreted after LPS stimulation, and a T cell product expressed as part of the antigen-dependent activation response. We report herein that MIF also plays a critical role in the innate host response to staphylococcal and streptococcal exotoxins, In RAW 264.7 or elicited mouse peritoneal macrophages, peak MIF secretion was induced by concentrations of the staphylococcal toxic shock syndrome (TSS) toxin 1 (TSST-1) and the streptococcal pyrogenic exotoxin A as low as 10 pg/ml, Moreover, dose-response studies of splenocyte cytokine production showed that lower concentrations of TSST-1 (10 pg/ml) were needed to release MIF than to induce interleukin 2 or interferon-gamma secretion (1 ng/ml), We also studied the effect of neutralizing anti MIF antibodies on TSST-1-induced lymphocyte proliferation and lethal toxic shock. Pretreatment of C57BL/6 mice with anti-MIF antibody 2 hr before TSST-1 injection prevented spleen enlargement and reduced by 50% the proliferation of splenocytes measured ex vivo. In. a lethal mouse model of TSST-1-induced shock, anti-MIF antibody increased survival from 8% to 54% (P < 0.0001). These studies indicate that Gram-positive exotoxins are extremely potent inducers of MIF secretion and establish a critical role for MIF and the macrophage in the pathogenesis of the TSSs and in the innate immune response.