Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model
Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model
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DOI：
10.1097/ccm.0b013e318211ff56
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发表时间：
2011-06-01
影响因子：
8.8
通讯作者：
Waetzig, Georg H.
中科院分区：
文献类型：
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作者：
Barkhausen, Tanja;Tschernig, Thomas;Waetzig, Georg H.
目的：多效性细胞因子白细胞介素（IL）-6似乎在脓毒症中起着关键作用，但动物模型中的矛盾发现阻碍了针对IL-6的治疗的基本原理。IL-6通过两种机制经由普遍存在的跨膜糖蛋白130（gp 130）进行信号传导：使用膜结合的IL-6受体（IL-6 R）的“经典”信号传导和使用可溶性IL-6 R（sIL-6 R）的反式信号传导。可溶性gp 130（sgp 130）选择性抑制反式信号传导。本研究的目的是系统地比较完全阻断IL-6信号传导（使用中和抗IL-6抗体）和选择性阻断IL-6反式信号传导（使用sgp 130和免疫球蛋白G1的可结晶片段sgp 130 Fc的融合蛋白）在标准化盲肠结扎和穿孔（CLP）脓毒症模型中的作用。设计：动物研究。设置：动物实验室。受试者：干预：我们进行了96小时剂量反应研究和24小时研究，以调查短期机制。在96小时研究中，在120只随机小鼠中进行CLP（20只小鼠接受溶剂，每个剂量组10只小鼠）。在CLP前24小时，用等摩尔剂量的sgp 130 Fc（0.01/0.1/1/10 mg/kg）或抗IL-6（0.008/0.08/0.8/8 mg/kg）治疗小鼠。另外两个组在CLP前24小时接受0.5 mg/kg sgp 130 Fc或在CLP后24小时接受1 mg/kg sgp 130 Fc。每天获得存活和活动评分，直到CLP后96小时。在24小时研究中，将小鼠随机分为四组，每组10只动物（假手术/载体、CLP/载体、CLP/抗IL-6 [0.8 mg/kg]和CLP/sgp 130 Fc [ 1 mg/kg]），并在24小时后处死。测量和主要结果：与抗IL-6相比，用sgp 130 Fc预处理显著且剂量依赖性地将存活率从45%增加至100%。此外，CLP后24小时给予1 mg/kg sgp 130 Fc使存活率从45%增加至80%。从机制上讲，sgp 130 Fc的功效体现在完全预防CLP后空肠上皮细胞凋亡，而抗IL-6则无法实现这一点。结论：sgp 130 Fc选择性抑制IL-6反式信号传导对于治疗脓毒症及相关疾病具有相当大的潜力。(Crit Care Med 2011; 39：1407-1413）
Objective: The pleiotropic cytokine interleukin (IL)-6 seems to play a pivotal role in sepsis, but contradictory findings in animal models impede a rationale for therapies directed against IL-6. IL-6 signals by two mechanisms via the ubiquitous transmembrane glycoprotein 130 (gp130): "classic" signaling using membrane-bound IL-6 receptor (IL-6R) and trans-signaling using soluble IL-6R (sIL-6R). Trans-signaling is selectively inhibited by soluble gp130 (sgp130). The aim of this study was to systematically compare complete blockade of IL-6 signaling (using a neutralizing anti-IL-6 antibody) and selective blockade of IL-6 trans-signaling (using a fusion protein of sgp130 and the crystallizable fragment of immunoglobulin G1, sgp130Fc) in a standardized cecal ligation and puncture (CLP) sepsis model.Design: Animal study.Setting: Animal laboratory.Subjects: C57BL/6J mice.Interventions: We performed a 96-hr dose-response study and a 24-hr study to investigate short-term mechanisms. In the 96-hr study, CLP was performed in 120 randomized mice (20 mice received vehicle, 10 mice per dose group). Mice were treated with equimolar doses of sgp130Fc (0.01/0.1/1/10 mg/kg) or anti-IL-6 (0.008/0.08/0.8/8 mg/kg) 24 hrs before CLP. Two additional groups received 0.5 mg/kg sgp130Fc 24 hrs before or 1 mg/kg sgp130Fc 24 hrs after CLP. Survival and activity scores were obtained daily until 96 hrs after CLP. In the 24-hr study, mice were randomized into four groups with 10 animals each (sham/vehicle, CLP/vehicle, CLP/anti-IL-6 [0.8 mg/kg], and CLP/sgp130Fc [ 1 mg/kg]) and killed after 24 hrs.Measurements and Main Results: In contrast to anti-IL-6, pretreatment with sgp130Fc significantly and dose-dependently increased survival from 45% to 100%. In addition, 1 mg/kg sgp130Fc administered 24 hrs after CLP increased survival from 45% to 80%. Mechanistically, sgp130Fc efficacy was reflected by complete prevention of epithelial cell apoptosis in the jejunum after CLP, which was not achieved with anti-IL-6.Conclusion: Selective inhibition of IL-6 trans-signaling by sgp130Fc has considerable potential for the treatment of sepsis and related disorders. (Crit Care Med 2011; 39: 1407-1413)