6-Gingerol attenuates macrophages pyroptosis via the inhibition of MAPK signaling pathways and predicts a good prognosis in sepsis
6-Gingerol attenuates macrophages pyroptosis via the inhibition of MAPK signaling pathways and predicts a good prognosis in sepsis
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6-姜酚通过抑制 MAPK 信号通路减轻巨噬细胞焦亡，并预测脓毒症的良好预后
DOI：
10.1016/j.cyto.2019.154854
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发表时间：
2020-01-01
期刊：
影响因子：
3.8
通讯作者：
Liu, Ke-Xuan
中科院分区：
文献类型：
--
作者：
Zhang, Fang-Ling;Zhou, Bo-Wei;Liu, Ke-Xuan
背景：脓毒症是ICU患者死亡的主要原因。脓毒症的发展在很大程度上取决于成熟IL-1 β细胞因子的存在。这项研究评估了一种名为6-姜辣素的生物活性化合物对脓毒症的潜在治疗特性。方法：采用盲肠结扎穿孔法（CLP）建立C57 B1/6小鼠脓毒症模型，观察其抗炎作用。在用6-姜辣素治疗后，我们评估了小鼠的存活率，并测量了血清和结肠组织中关键促炎细胞因子的水平。使用经ATP和脂多糖（LPS）处理的RAW264.7细胞系和骨髓衍生的巨噬细胞（BMDM）进一步探索脓毒症发病机制。还检查了6-姜辣素对焦亡的影响。此外，我们评估了MAPK信号通路在6-姜酚诱导的BMDM和RAW264.7细胞中的作用。结果：在CLP小鼠中，6-姜酚显著改善脓毒症的发展，这与血清IL-1 β的降低有关。在BMDM和RAW264.7细胞中，6-姜辣素强烈减弱了响应于ATP和LPS处理的焦亡以及caspase-1 p20、HMGB 1、成熟IL-1 β、IL-18的释放。6-姜辣素通过阻断MAPK的激活而发挥这些作用。暴露于ERK激动剂（EGF）逆转6-姜辣素的影响，引起pyroptosis，LDH和caspase-1 p20 release.Conclusions：通过靶向MAPK信号转导，6-姜辣素显着抑制促炎细胞因子的分泌，抑制巨噬细胞pyroptosis导致整体抑制脓毒症的发展。
Background: Sepsis is a major cause of death for ICU patients. Sepsis development depends heavily on the presence of mature IL-1 beta cytokine. This study evaluates the potential therapeutic properties of a bioactive compound known as 6-gingerol on sepsis. This compound has previously been demonstrated to possess anti-inflammatory properties both in vivo and in vitro.Methods: C57B1/6 mice was used to establish models of sepsis by means of cecal ligation and puncture (CLP). Upon treatment with 6-gingerol, we assessed the survival rate of mice and measured the levels of key pro-inflammatory cytokines in serum and colon tissues. Sepsis pathogenesis was further explored using the RAW264.7 cell line and bone marrow-derived macrophages (BMDMs) treated with ATP and lipopolysaccharide (LPS). The impact of 6-gingerol on pyroptosis was also examined. In addition, we assessed the role of MAPK signaling in 6-gingerol-induced effects in BMDMs and RAW264.7 cells.Results: In CLP mice, 6-gingerol significantly ameliorated sepsis development, which was associated with the reduction of serum IL-1 beta. In BMDMs and RAW264.7 cells, 6-gingerol strongly attenuated pyroptosis as well as the release of caspase-1p20, HMGB1, mature IL-1 beta, IL-18 in response to ATP and LPS treatment. 6-Gingerol conferred these effects by blocking MAPK activation. Exposure to an ERK agonist (EGF) reversed effects of 6-gingerol, causing pyroptosis, LDH and caspase-1p20 release.Conclusions: By targeting MAPK signaling, 6-gingerol significantly suppressed secretion of pro-inflammatory cytokines and inhibited macrophage cells pyroptosis resulting in overall inhibition of sepsis development.