TWEAK/Fn14 Pathway: A Nonredundant Role in Intestinal Damage in Mice Through a TWEAK/Intestinal Epithelial Cell Axis
TWEAK/Fn14 Pathway: A Nonredundant Role in Intestinal Damage in Mice Through a TWEAK/Intestinal Epithelial Cell Axis
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DOI：
10.1053/j.gastro.2008.11.017
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发表时间：
2009-03-01
期刊：
影响因子：
29.4
通讯作者：
Burkly, Linda C.
中科院分区：
文献类型：
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作者：
Dohi, Taeko;Borodovsky, Anna;Burkly, Linda C.
背景和目标：肿瘤坏死因子（TNF）超家族成员作为治疗炎症性疾病的新靶点引起了人们的关注。肿瘤坏死因子样弱凋亡诱导因子（TWEAK）是一种独特的、多功能的TNF家族细胞因子，通过其受体成纤维细胞生长因子诱导分子14（Fn 14）发出信号。该途径在肠道中的作用以前没有报道过。研究方法：在TWEAK或Fn 14缺陷小鼠或用TWEAK阻断性单克隆抗体处理的正常小鼠中进行2，4，6-三硝基苯磺酸（TNBS）诱导的结肠炎模型，并评估临床严重程度、组织病理学、细胞浸润、TWEAK和Fn 14的免疫组织化学、结肠中的基因表达谱和全身适应性免疫。体外分析TWEAK对结肠上皮细胞产生炎症介质的影响。在TWEAK或Fn 14缺陷小鼠中进行γ-辐射损伤模型，并评估隐窝上皮死亡。结果：TWEAK通路缺陷或TWEAK阻断单克隆抗体显著降低了结肠炎的严重程度和组织学评分。TNBS给药后，TWEAK缺陷结肠中的神经细胞和巨噬细胞浸润、趋化因子、细胞因子和基质金属蛋白酶表达减少;然而，对三硝基苯基的全身适应性免疫应答没有改变。TNBS结肠炎中Fn 14在结肠上皮细胞上表达，TWEAK诱导上皮产生致病介质。TWEAK还调节肠上皮更新，如TWEAK和Fn 14基因敲除小鼠中γ辐射损伤后上皮细胞死亡减少所证明的。结论：我们的研究阐明了非冗余的TWEAK-肠上皮细胞轴，并提示阻断TWEAK可能抑制慢性肠道炎症并允许正常的上皮修复。
Background and Aims: Tumor necrosis factor (TNF) superfamily members have attracted attention as new therapeutic targets for treating inflammatory disease. TNF-like weak inducer of apoptosis (TWEAK) is a unique, multifunctional TNF family cytokine that signals through its receptor, fibroblast growth factor-inducible molecule 14 (Fn14). The role of this pathway in the intestine has not been previously reported. Methods: The 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model was conducted in TWEAK- or Fn14-deficient mice or in normal mice treated with a TWEAK-blocking monoclonal antibody, and clinical severity, histopathology, immunohistochemistry for cell infiltrates, TWEAK and Fn14, gene expression profiling in the colon, and systemic adaptive immunity were assessed. The effect of TWEAK on colon epithelial cell production of inflammatory mediators was analyzed in vitro. The gamma-irradiation injury model was conducted in TWEAK- or Fn14-deficient mice, and crypt epithelial death was assessed. Results: Colitis severity and histologic scores were significantly reduced by TWEAK pathway deficiency or TWEAK-blocking monoclonal antibody. Neutrophil and macrophage infiltrates, chemokines, cytokines, and matrix metalloproteinase expression were reduced in the TWEAK-deficient colon after TNBS administration; however, systemic adaptive immune responses to trinitrophenyl were not altered. Fn14 is expressed on colon epithelial cells in TNBS colitis, and TWEAK induces epithelial production of pathogenic mediators. TWEAK also regulates intestinal epithelial turnover, as evidenced by reduced epithelial cell death after gamma-irradiation injury in TWEAK and Fn14 knockout mice. Conclusions: our studies elucidate a nonredundant TWEAK-intestinal epithelial cell axis and suggest that blocking TWEAK may dampen chronic intestinal inflammation and allow normal epithelial repair.