Penta-O-galloyl-β-D-glucose ameliorates inflammation by inhibiting MyD88/NF-κB and MyD88/MAPK signalling pathways
Penta-O-galloyl-β-D-glucose ameliorates inflammation by inhibiting MyD88/NF-κB and MyD88/MAPK signalling pathways
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DOI：
10.1111/bph.12333
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发表时间：
2013-11-01
影响因子：
7.3
通讯作者：
Kim, Dong-Hyun
中科院分区：
文献类型：
--
作者：
Jang, Se-Eun;Hyam, Supriya R.;Kim, Dong-Hyun
背景与目的：盐肤木五倍子及其主要成分五-O-没食子酰-D-葡萄糖（penta-O-galloyl-D-glucose，PGG）可抑制LPS刺激的腹腔和结肠巨噬细胞NF-B活化。实验方法雄性C57 BL/6小鼠（18- 22 g，6周龄）制备腹腔巨噬细胞和结肠巨噬细胞，直肠内给予2，3，4-三硝基苯磺酸（TNBS）诱导结肠炎。ELISA，免疫印迹，流式细胞术和共聚焦microscopic.Key ResultsToll样受体（TLR）-4或脂多糖（LPS）结合TLR-4在LPS刺激的腹腔巨噬细胞的表达的炎症标志物和转录因子的范围进行了评估，PGG不受影响。然而，PGG抑制抗MyD 88抗体与腹膜巨噬细胞的结合，但在用或不用MyD 88 siRNA转染的情况下不降低抗IL-1受体相关激酶（IRAK 1）和IRAK 4抗体与巨噬细胞的结合。PGG有效地降低了LPS或肽聚糖刺激的腹膜和结肠巨噬细胞中IRAK 1、NF-B和MAPK的活化。PGG抑制LPS刺激的腹腔巨噬细胞中的IL-1、TNF-α和IL-6，同时增加抗炎细胞因子IL-10的表达。口服PGG可抑制TNBS诱导的结肠炎小鼠的结肠缩短和髓过氧化物酶活性，沿着降低NF-B活化和IL-1、TNF-α和IL-6水平，同时升高IL-10水平。结论和意义PGG通过直接与MyD 88衔接蛋白相互作用，降低NF-B和MAPK信号通路的活化。PGG可以改善炎症性疾病，如结肠炎。
Background and PurposeThe gallnut of Rhus chinensisMILL and its main constituent penta-O-galloyl--D-glucose (PGG) inhibited NF-B activation in LPS-stimulated peritoneal and colonic macrophages. Here we have investigated PGG mechanisms underlying anti-inflammatory effects of PGG in vitro and in vivo.Experimental ApproachMale C57BL/6 mice (18-22g, 6 weeks old) were used to prepare peritoneal and colonic macrophages and for the induction of colitis by intrarectal administration of 2,3,4-trinitrobenzene sulphonic acid (TNBS). A range of inflammatory markers and transcription factors were evaluated by elisa, immunoblotting, flow cytometry and confocal microscopy.Key ResultsExpression of Toll-like receptor (TLR)-4 or Lipopolysaccharide (LPS) binding to TLR-4 in LPS-stimulated peritoneal macrophages was not affected by PGG. However PGG inhibited binding of an anti-MyD88 antibody to peritoneal macrophages, but did not reduce binding of anti-IL-1 receptor-associated kinase (IRAK1) and IRAK4 antibodies to the macrophages with or without transfection with MyD88 siRNA. PGG potently reduced the activation of IRAK1, NF-B, and MAPKs in LPS- or pepetidoglycan-stimulated peritoneal and colonic macrophages. PGG suppressed IL-1, TNF- and IL-6 in LPS-stimulated peritoneal macrophages, while increasing expression of the anti-inflammatorycytokine IL-10. Oral administration of PGG inhibited colon shortening and myeloperoxidase activity in mice with TNBS-induced colitis, along with reducing NF-B activation and IL-1, TNF-, and IL-6 levels, whereas it increased IL-10.Conclusions and ImplicationsPGG reduced activation of NF-B and MAPK signalling pathways by directly interacting with the MyD88 adaptor protein. PGG may ameliorate inflammatory diseases such as colitis.