The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle
The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle
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DOI：
10.1172/jci9900
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发表时间：
2000-11-01
影响因子：
15.9
通讯作者：
Bucala, R
中科院分区：
文献类型：
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作者：
Benigni, F;Atsumi, T;Bucala, R
严重的感染或组织侵入可引起分解代谢反应，导致严重的代谢紊乱、恶病质，甚至死亡。巨噬细胞移动抑制因子（MIF）是宿主对感染反应的重要调节因子。MIF由各种免疫细胞和垂体前叶释放，通过抵消糖皮质激素对免疫细胞活化和促炎细胞因子产生的抑制作用，在全身炎症反应中起关键作用。我们在此描述了一个意想不到的作用，MIF在糖酵解的调节。此外，MIF分化的L 6大鼠肌管增加果糖2，6-二磷酸（F2，6 BP），糖酵解的正变构调节剂的合成。6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶（PFK-2）的表达增加可增强F2，6 BP的产生，从而增强细胞乳酸盐的产生。TNF-α对肌管的分解代谢作用由MIF介导，MIF作为F2，6 BP产生的自分泌刺激。给予小鼠TNF-α可降低血清葡萄糖水平并增加肌肉F2，6 BP水平;用中和性抗MIF mAb预处理可完全抑制这些作用。抗MIF还可预防低血糖，并增加给予LPS的TNF-α-敲除小鼠的肌肉F2，6 BP水平，支持MIF对这些炎症诱导的代谢变化的内在贡献。结合最近发现MIF是一种积极的胰岛素释放自分泌刺激剂，这些数据表明MIF在控制宿主葡萄糖处置和碳水化合物代谢中起重要作用。
Severe infection or tissue invasion can provoke a catabolic response, leading to severe metabolic derangement, cachexia, and even death. Macrophage migration inhibitory factor (MIF) is an important regulator of the host response to infection. Released by various immune cells and by the anterior pituitary gland, MIF plays a critical role in the systemic inflammatory response by counterregulating the inhibitory effect of glucocorticoids on immune-cell activation and proinflammatory cytokine production. We describe herein an unexpected role for MIF in the regulation of glycolysis. The addition of MIF to differentiated L6 rat myotubes increased synthesis of fructose 2,6-bisphosphate (F2,6BP), a positive allosteric regulator of glycolysis. Increased expression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) enhanced F2,6BP production and, consequently, cellular lactate production. The catabolic effect of TNF-alpha on myotubes was mediated by MIF, which served as an autocrine stimulus for F2,6BP production. TNF-alpha administered to mice decreased serum glucose levels and increased muscle F2,6BP levels; pretreatment with a neutralizing anti-MIF mAb completely inhibited these effects. Anti-MIF also prevented hypoglycemia and increased muscle F2,6BP levels in TNF-alpha -knockout mice that were administered LPS, supporting the intrinsic contribution of MIF to these inflammation-induced metabolic changes. Taken together with the recent finding that MIF is a positive, autocrine stimulator of insulin release, these data suggest an important role for MIF in the control of host glucose disposal and carbohydrate metabolism.