Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells.
Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells.
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DOI：
10.1016/j.jhep.2015.12.020
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发表时间：
2016-05
影响因子：
25.7
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Yan J;Mitra A;Hu J;Cutrera JJ;Xia X;Doetschman T;Gagea M;Mishra L;Li S
脓毒症是一种急性全身性炎症反应感染与高患者死亡率（28-40%）。我们假设，白细胞介素（IL）-30，一种新的细胞因子，保护小鼠免受炎症引起的肝损伤，将产生对全身炎症和脓毒症诱导的死亡的保护作用。脓毒症由脂多糖（LPS）或盲肠结扎穿孔（CLP）诱导。在野生型、IL-30（p28）−/−、IL-10 −/−和CD 1d −/−小鼠中测定IL-30对脓毒性炎症的抑制作用和相关治疗作用。pIL-30基因治疗或重组IL-30蛋白（rIL-30）治疗的小鼠可保护免于LPS诱导的脓毒性休克或CLP诱导的多微生物脓毒症，并且显示出比对照脓毒症小鼠明显更少的肝损伤和淋巴细胞凋亡。死亡率的降低是通过全身促炎反应的减弱和细菌清除的增加来介导的。缺乏IL-30的小鼠对LPS诱导的脓毒症更敏感。与对照败血症小鼠相比，IL-30处理的败血症小鼠中的天然免疫细胞样T细胞（NKT）产生更高水平的IL-10和更低水平的干扰素-γ和肿瘤坏死因子-α。同样地，IL-10或NKT细胞的缺乏也消除了IL-30对脓毒症的保护作用。此外，IL-30诱导纯化和LPS刺激的NKT细胞中IL-10的产生。阻断IL-6 R或gp 130可抑制IL-30介导的IL-10产生。IL-30在调节NKT细胞因子的产生和随后的NKT细胞介导的其他细胞的免疫调节中是重要的。因此，IL-30通过调节NKT产生的细胞因子在预防和治疗脓毒症中具有作用。
Sepsis is an acute systemic inflammatory response to infection associated with high patient mortality (28-40%). We hypothesized that interleukin (IL)-30, a novel cytokine protecting mice against liver injury resulted from inflammation, would generate a protective effect against systemic inflammation and sepsis-induced death. Sepsis was induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). The inhibitory effects of IL-30 on septic inflammation and associated therapeutic effects were determined in wild-type, IL-30 (p28)−/−, IL10−/−, and CD1d−/− mice. Mice treated with pIL30 gene therapy or recombinant IL-30 protein (rIL30) were protected from LPS-induced septic shock or CLP-induced polymicrobial sepsis and showed markedly less liver damage and lymphocyte apoptosis than control septic mice. The resulting reduction in mortality was mediated through attenuation of the systemic pro-inflammatory response and augmentation of bacterial clearance. Mice lacking IL-30 were more sensitive to LPS-induced sepsis. Natural killer–like T cells (NKT) produced much higher levels of IL-10 and lower levels of interferon–gamma and tumor necrosis factor–alpha in IL-30–treated septic mice than in control septic mice. Likewise, deficiency in IL-10 or NKT cells abolished the protective role of IL-30 against sepsis. Furthermore, IL-30 induced IL-10 production in purified and LPS-stimulated NKT cells. Blocking IL-6R or gp130 inhibited IL-30 mediated IL-10 production. IL-30 is important in modulating production of NKT cytokines and subsequent NKT cell–mediated immune regulation of other cells. Therefore, IL-30 has a role in prevention and treatment of sepsis via modulation of cytokine production by NKT.