Seselin ameliorates inflammation via targeting Jak2 to suppress the proinflammatory phenotype of macrophages
Seselin ameliorates inflammation via targeting Jak2 to suppress the proinflammatory phenotype of macrophages
复制标题
Seselin 通过靶向 Jak2 抑制巨噬细胞的促炎表型来改善炎症。
DOI：
10.1111/bph.14521
复制
发表时间：
2019-01-01
影响因子：
7.3
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Feng, Lili;Sun, Yi;Xu, Qiang
背景与目的脓毒症是一种严重的临床疾病，病死率高。抗炎药被发现对脓毒症的治疗是有益的。在这里，我们评估了芝麻素在脓毒症模型中的抗炎活性，并探讨了其潜在的分子机制(S)。实验方法在C57BL/6小鼠盲肠结扎和穿孔或注射脂多糖两种脓毒症模型上，观察芝麻素的体内治疗作用。在体外，用脂多糖和干扰素-γ刺激巨噬细胞来评价芝麻素的抗炎活性。采用免疫组织化学、酶联免疫吸附试验和免疫印迹等方法分析其抗炎作用。用流式细胞术检测巨噬细胞表型(促炎症或抗炎)的标志物。其他使用的方法包括免疫共沉淀、细胞热位移分析和分子对接。主要结果在体内，芝麻素明显改善盲肠结扎和穿孔所致的脓毒症。在脓毒症小鼠的肺组织和培养的巨噬细胞中，芝麻素下调促炎因子的水平和STAT1和P65的活性，STAT1和P65是巨噬细胞极化进入促炎表型的主要信号途径分子。重要的是，过继转移骨髓来源的巨噬细胞，用芝麻素预处理，降低了内毒素攻击小鼠的全身促炎因子。其潜在机制是，芝麻素以JAK2为靶点，阻断了与干扰素-γ受体和下游STAT1的相互作用。结论和启示：Seselin通过对JAK2的作用显示出抗炎活性。这些结果表明，芝麻素可能通过阻断巨噬细胞的致炎表型而用于炎症性疾病的治疗。
Background and Purpose Sepsis is a serious clinical condition with a high mortality rate. Anti inflammatory agents have been found to be beneficial for the treatment of sepsis. Here, we have evaluated the anti-inflammatory activity of seselin in models of sepsis and investigated the underlying molecular mechanism(s). Experimental Approach In vivo therapeutic effects of seselin was evaluated in two models of sepsis, caecal ligation and puncture or injection of LPS, in C57BL/6 mice. In vitro, anti-inflammatory activity of seselin was assessed with macrophages stimulated with LPS and IFN-gamma. Anti inflammatory actions were analysed with immunohistochemical methods, ELISA and Western blotting. Flow cytometry was used to assess markers of macrophage phenotype (pro- or anti-inflammatory). Other methods used included co-immunoprecipitation, cellular thermal shift assay and molecular docking. Key Results In vivo, seselin clearly ameliorated sepsis induced by caecal ligation and puncture. In lung tissue from septic mice and in cultured macrophages, seselin down-regulated levels of proinflammatory factors and activity of STAT1 and p65, the master signal pathway molecules for polarization of macrophages into the proinflammatory phenotype. Importantly, adoptive transfer of bone marrow-derived macrophages, pretreated with seselin, lowered systemic proinflammatory factors in mice challenged with LPS. The underlying mechanism was that seselin targeted Jak2 to block interaction with IFN gamma receptors and downstream STAT1. Conclusions and Implications Seselin exhibited anti-inflammatory activity through its action on Jak2. These results indicated a possible application of seselin to the treatment of inflammatory disease via blocking the development of the proinflammatory phenotype of macrophages.