Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27.
Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27.
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通过中和白细胞介素的生物学功能27来保护致死性败血性腹膜炎。
DOI：
10.1084/jem.20060471
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发表时间：
2006-08-07
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必须严格控制对细菌感染的免疫反应，以保证病原体消除，同时防止不受控制的炎症造成组织损伤。在这里，我们证明了白细胞介素(IL)-27在调节这种关键平衡中的关键作用。IL-27在盲肠结扎穿刺（CLP）小鼠实验性腹膜炎中快速诱导。此外，与野生型对照相比，缺乏IL-27 EBI3亚基的小鼠对clp诱导的脓毒性腹膜炎具有抗性，并且可以通过注射重组单链IL-27来抑制这种作用。EBI3−/−小鼠在CLP期间表现出显著增强的中性粒细胞迁移和氧化爆发能力，从而增强细菌清除和局部感染控制。随后的研究表明，IL-27直接抑制内毒素诱导的原代粒细胞和巨噬细胞产生活性氧中间体。最后，使用新设计的可溶性IL-27受体融合蛋白在体内阻断IL-27功能，与对照组相比，CLP后小鼠的存活率显着提高。总的来说，这些数据确定IL-27是败血性腹膜炎先天免疫细胞功能的关键负调节因子。此外，体内阻断IL-27是治疗败血症的一个新的潜在治疗靶点。
The immune response to bacterial infections must be tightly controlled to guarantee pathogen elimination while preventing tissue damage by uncontrolled inflammation. Here, we demonstrate a key role of interleukin (IL)-27 in regulating this critical balance. IL-27 was rapidly induced during murine experimental peritonitis induced by cecal ligation and puncture (CLP). Furthermore, mice deficient for the EBI3 subunit of IL-27 were resistant to CLP-induced septic peritonitis as compared with wild-type controls, and this effect could be suppressed by injection of recombinant single-chain IL-27. EBI3−/− mice displayed significantly enhanced neutrophil migration and oxidative burst capacity during CLP, resulting in enhanced bacterial clearance and local control of infection. Subsequent studies demonstrated that IL-27 directly suppresses endotoxin-induced production of reactive oxygen intermediates by isolated primary granulocytes and macrophages. Finally, in vivo blockade of IL-27 function using a newly designed soluble IL-27 receptor fusion protein led to significantly increased survival after CLP as compared with control-treated mice. Collectively, these data identify IL-27 as a key negative regulator of innate immune cell function in septic peritonitis. Furthermore, in vivo blockade of IL-27 is a novel potential therapeutic target for treatment of sepsis.