Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation
Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation
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DOI：
10.1136/gutjnl-2013-305005
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发表时间：
2014-08-01
期刊：
影响因子：
24.5
通讯作者：
Steardo, Luca
中科院分区：
文献类型：
--
作者：
Esposito, Giuseppe;Capoccia, Elena;Steardo, Luca
目的研究肠神经胶质细胞活化通过肠神经胶质细胞特异性S100 B蛋白放大肠道炎症反应。这种神经营养因子促进粘膜中巨噬细胞的募集，放大结肠炎症并与toll样受体（TLR）相互作用。抑制S100 B驱动的肠道激活的分子可能会减轻溃疡性结肠炎（UC）的进程。本研究旨在研究棕榈酰乙醇胺（PEA）（一种能够对抗中枢神经系统中星形胶质细胞活化的药物）对人类和小鼠肠道炎症的影响。设计葡聚糖硫酸钠（DSS）诱导的结肠炎的小鼠模型、来自UC患者的结肠活检以及小鼠和人类肠道胶质细胞（EGC）的原代培养物已用于评估PEA的作用，单独或在特定的PPARalpha或PPARgamma拮抗剂存在下，对UC的宏观体征（DAI评分、结肠长度、脾重量、巨噬细胞/嗜中性粒细胞浸润）; UC典型的促炎标志物的表达和释放; EGCs中的TLR途径。PEA的抗炎作用是通过选择性靶向ECG上的S100 B/TLR 4轴介导的，从而引起对核因子κ B（NF-kB）依赖性炎症的下游抑制。拮抗剂在PPAR α，但不是PPAR γ，废除PEA的影响，在小鼠和human.Conclusions，由于其缺乏毒性，其能力，在减少炎症和选择性的PPAR α作用，PEA可能是一个创新的分子，以扩大对UC的药理学策略。
Objective Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice.Design Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPAR alpha or PPAR gamma antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs.Results PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPAR alpha, but not PPAR gamma, abolished PEA effects, in mice and in humans.Conclusions Because of its lack of toxicity, its ability in reducing inflammation and its selective PPAR alpha action, PEA might be an innovative molecule to broaden pharmacological strategies against UC.