Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol.
Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol.
复制标题
DOI：
10.1371/journal.pone.0159459
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Erle DJ
中科院分区：
文献类型：
--
作者：
Khosravi AR;Erle DJ
甲壳素由真菌、昆虫和其他生物体大量产生，与哮喘的发病机制有关。呼吸道上皮细胞与环境颗粒直接接触，是抵御吸入过敏原和病原体的第一道防线。呼吸道上皮细胞在甲壳素诱导的哮喘中的潜在作用仍然知之甚少。我们假设甲壳素直接刺激呼吸道上皮细胞释放促进2型免疫反应的细胞因子，并诱导在先天性免疫反应中重要的分子的表达。我们发现，甲壳素暴露能迅速诱导BEAS-2B转化的人支气管上皮细胞、A549和H292肺癌细胞中三种关键的2型促进细胞因子IL-25、IL-33和TSLP的表达。甲壳素还诱导了关键的模式识别受体TLR2和TLR4的表达。甲壳素诱导miR-155、miR-146a和miR-21的表达，其中每一种都能上调促炎细胞因子的表达。几丁质还抑制了miR-155的已知靶点SOCS1和SHIP1的表达。单萜苯酚香芹酚(CAR)及其异构体百里香酚(THY)存在于草本精油中，已被证明可抑制哮喘模型中的过敏性炎症。我们发现CAR/THY抑制了甲壳素促进2型细胞因子的释放以及对TLRs、SOCS1、SHIP1和miRNAs表达的影响。CAR/THY还能有效降低TLR4的蛋白水平，抑制几丁质加CAR/THY处理的细胞TLR2蛋白水平的升高，增加TLR介导的炎症反应的负调控因子SHIP1和SOCS1的蛋白水平。我们的结论是，甲壳素对呼吸道上皮细胞的直接作用可能导致哮喘等过敏性呼吸道疾病，而CAR/THY直接抑制上皮细胞对甲壳素的促炎反应。
Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin.