Emergency Department of Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning Province 110004, China.
Emergency Department of Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning Province 110004, China.
Life Sci. 2017 Sep 15;185:85-94. doi: 10.1016/j.lfs.2017.07.010. Epub 2017 Jul 12.
Sepsis-triggered immune paralysis including T-cell dysfunction increase susceptibility to infection. Gamma interferon (IFNg) exert beneficial effects in patients with sepsis. Herein, we speculated that IFNg may attenuate T-cell dysfunction induced by sepsis, although the mechanisms remain elusive. To test this hypothesis, we used a model based on cecal ligation and puncture (CLP) to induce sepsis in mice.
Male C57BL/6 mice were pretreated with recombinant human IFNg (0.01μg/g of body weight) before CLP. The immunophenotyping of cell surface receptor expression, and regulatory T cells (CD4+CD25+Foxp3+) were quantified by flow cytometry. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. Formation of IFNg and interleukin 4 (IL-4) in the spleen and plasma levels of TNF-α, IL-6, high-mobility group box 1 (HMGB1) were determined using enzyme-linked immunosorbent assay.
IFNg markedly inhibited the reduction in cytokine secretion from lipopolysaccharide (LPS)-stimulated splenocytes. IFNg-treated mices had significantly decreased percentages of programmed cell death 1 (PD-1) receptors, increased the percentages of positive costimulatory receptor CD28 on CD4 T cells expressing. IFNg markedly reduced T-cell apoptosis through upregulating the expression of Bcl-2. CLP-induced formation of regulatory T cells in the spleen was abolished in IFNg -treated mices. Moreover, IFNg treatment reduced plasma levels of TNF-α, IL-6, HMGB1.
IFNg can be a powerful regulator of immune function under sepsis conditions. Therefore, targeted immune-enhancement with IFNg may be a valid therapeutic approach in sepsis.
脓毒症引发的免疫麻痹包括 T 细胞功能障碍会增加感染易感性。γ干扰素（IFNg）对脓毒症患者具有有益作用。在此，我们推测 IFNg 可能减轻脓毒症引起的 T 细胞功能障碍，尽管其机制尚不清楚。为了验证这一假设，我们使用盲肠结扎穿孔（CLP）模型在小鼠中诱导脓毒症。
雄性 C57BL/6 小鼠在 CLP 前用重组人 IFNg（0.01μg/g 体重）预处理。通过流式细胞术定量细胞表面受体表达和调节性 T 细胞（CD4+CD25+Foxp3+）的免疫表型。通过免疫组织化学染色评估免疫效应细胞的丢失。通过酶联免疫吸附试验测定脾和血浆中 IFNg 和白细胞介素 4（IL-4）的形成以及 TNF-α、IL-6、高迁移率族蛋白 1（HMGB1）的水平。
IFNg 显著抑制脂多糖（LPS）刺激的脾细胞细胞因子分泌减少。IFNg 处理的小鼠程序性死亡受体 1（PD-1）受体的百分比显著降低，CD4 T 细胞上的共刺激受体 CD28 的阳性百分比增加。IFNg 通过上调 Bcl-2 的表达显著减少 T 细胞凋亡。IFNg 处理可消除 CLP 诱导的脾中调节性 T 细胞的形成。此外，IFNg 治疗可降低血浆中 TNF-α、IL-6、HMGB1 的水平。
IFNg 可成为脓毒症条件下免疫功能的有力调节剂。因此，针对 IFNg 的靶向免疫增强可能是脓毒症的一种有效治疗方法。
