Fagundes Caio T, Amaral Flávio A, Souza Adriano L S, Vieira Angélica T, Xu Damo, Liew Foo Y, Souza Danielle G, Teixeira Mauro M
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627-Pampulha, 31270-901 Belo Horizonte, MG, Brazil.
J Leukoc Biol. 2007 Feb;81(2):492-9. doi: 10.1189/jlb.0606422. Epub 2006 Nov 10.
Ischemia reperfusion injury is characterized by local and systemic inflammation leading to considerable mortality. Previously, we have reported that soluble T1/ST2 (sST2), a member of the IL-1 receptor gene family, inhibits LPS-induced macrophage proinflammatory cytokine production. Here, we report the therapeutic effect of sST2-Fc in a murine model of intestinal ischemia reperfusion-induced injury. Administration of sST2-Fc fusion protein i.v., 10 min before reperfusion, reduced the production of TNF-alpha dose-dependently in the intestine and in the lungs. The sST2-Fc treatment with the highest dose (100 mug) resulted in inhibited vascular permeability, neutrophilia, and hemorrhage in the intestine and the lungs compared with controls treated with normal IgG. This was associated with down-regulated tissue levels of proinflammatory cytokines, markedly reduced serum TNF-alpha levels, and increased survival of mice from the sST2-Fc-treated group after ischemia and reperfusion injury. The beneficial effect of sST2-Fc treatment was associated with elevated IL-10 production in intestine and lung. sST2-Fc was not able to prevent the inflammatory response associated with intestinal ischemia and reperfusion in IL-10-deficient mice, suggesting that sST2 exerts its anti-inflammatory effect in a IL-10-dependent manner. These results also demonstrate that sST2-Fc may provide a novel, complementary approach in treating ischemic reperfusion injury.
缺血再灌注损伤的特征是局部和全身炎症，可导致相当高的死亡率。此前，我们曾报道，IL-1受体基因家族成员可溶性T1/ST2（sST2）可抑制脂多糖诱导的巨噬细胞促炎细胞因子生成。在此，我们报道了sST2-Fc在小鼠肠道缺血再灌注诱导损伤模型中的治疗作用。在再灌注前10分钟静脉注射sST2-Fc融合蛋白，可使肠道和肺部的肿瘤坏死因子-α（TNF-α）生成呈剂量依赖性减少。与用正常IgG处理的对照组相比，最高剂量（100μg）sST2-Fc处理可抑制肠道和肺部的血管通透性、中性粒细胞增多及出血。这与促炎细胞因子的组织水平下调、血清TNF-α水平显著降低以及sST2-Fc处理组小鼠在缺血再灌注损伤后的存活率增加有关。sST2-Fc治疗的有益作用与肠道和肺部IL-10生成增加有关。在IL-10缺陷小鼠中，sST2-Fc无法预防与肠道缺血再灌注相关的炎症反应，这表明sST2以IL-10依赖的方式发挥其抗炎作用。这些结果还表明，sST2-Fc可能为治疗缺血再灌注损伤提供一种新的补充方法。
