TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis.
TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis.
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与TNF相关的凋亡诱导配体（TRAIL）调节中线1，胸腺基质淋巴细胞生成素，炎症和重塑实验性嗜酸性粒细胞性食管炎。
DOI：
10.1016/j.jaci.2015.03.031
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Mattes J
中科院分区：
文献类型：
--
作者：
Collison AM;Sokulsky LA;Sherrill JD;Nightingale S;Hatchwell L;Talley NJ;Walker MM;Rothenberg ME;Mattes J
嗜酸性粒细胞性食管炎 (EoE) 是一种食管炎症性疾病，表现为嗜酸性粒细胞浸润和组织重塑，从而导致食管功能障碍的症状。肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 通过上调 E3 泛素连接酶 midline-1 (MID1) 促进炎症，MID1 与蛋白磷酸酶 2 A (PP2Ac) 的催化亚基结合并使其失活，导致 NF-κB 激活增加。阐明 TRAIL 在 EoE 中的作用。我们使用烟曲霉 (Asp F) 在 TRAIL 充足（野生型）和缺陷 (−/−) 小鼠中诱导 EoE，并用小干扰 (si) RNA 靶向食道中的 MID1。我们还用重组 TSLP 和 TRAIL 治疗小鼠。 TRAIL 缺陷和使用 siRNA 沉默 MID1 可减少食管嗜酸性粒细胞和肥大细胞数量，并防止食管周长增大、外肌层增厚和胶原沉积。与野生型对照相比，TRAIL−/− 小鼠中的 MID1 表达和 NF-κB 激活减少，而 PP2Ac 水平增加。这与 CCL24、CCL11、CCL20、IL-5、IL-13、IL-25、TGF-β 和 TSLP 的表达减少有关。 TSLP 治疗重建了 TRAIL−/− 小鼠 EoE 的标志性特征，并且重组 TRAIL 在没有过敏原的情况下诱导体内食管 TSLP 表达。基因阵列数据的事后分析表明，与患病对照相比，EoE 儿童队列中 TRAIL 和 MID1 显着上调。 TRAIL 在实验 EoE 中调节 MID1 和 TSLP、炎症、纤维化、平滑肌肥大以及炎症效应趋化因子和细胞因子的表达。
Eosinophilic Oesophagitis (EoE) is an inflammatory disorder of the oesophagus defined by eosinophil infiltration and tissue remodelling with resulting symptoms of oesophageal dysfunction. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes inflammation by upregulation of the E3 ubiquitin-ligase midline-1 (MID1), which binds to and deactivates the catalytic subunit of protein phosphatase 2 A (PP2Ac) resulting in increased NF-κB activation. To elucidate the role of TRAIL in EoE. We used Aspergillus fumigatus(Asp F) to induce EoE in TRAIL sufficient (wildtype) and deficient (−/−) mice and targeted MID1 in the oesophagus with small interfering (si) RNA. We also treated mice with recombinant TSLP and TRAIL. TRAIL deficiency and MID1 silencing employing siRNA reduced oesophageal eosinophil and mast cell numbers and protected from oesophageal circumference enlargement, muscularis externa thickening and collagen deposition. MID1 expression and NF-κB activation were reduced in TRAIL−/− mice, while PP2Ac levels were increased compared to wildtype controls. This was associated with reduced expression of CCL24, CCL11, CCL20, IL-5, IL-13, IL-25, TGF-β and TSLP. Treatment with TSLP reconstituted hallmark features of EoE in TRAIL−/− mice and recombinant TRAIL induced oesophageal TSLP expression in vivo in the absence of allergen. Post hoc analysis of gene array data demonstrated a significant upregulation of TRAIL and MID1 in a cohort of children with EoE as compared to diseased controls. TRAIL regulates MID1 and TSLP, inflammation, fibrosis, smooth muscle hypertrophy and expression of inflammatory effector chemokines and cytokines in experimental EoE.