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首页> 外文期刊>Cytokine >Pathological activation of canonical nuclear-factor κB by synergy of tumor necrosis factor α and TNF-like weak inducer of apoptosis in mouse acute colitis
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Pathological activation of canonical nuclear-factor κB by synergy of tumor necrosis factor α and TNF-like weak inducer of apoptosis in mouse acute colitis

机译：肿瘤坏死因子α和TNF样弱凋亡诱导剂协同作用在小鼠急性结肠炎中激活经典核因子κB

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摘要

Tumor necrosis factor (TNF)-α is a major effector in various inflammatory conditions. TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that promotes inflammatory tissue damage through its receptor, FGF-inducible molecule 14 (Fn14). Since both TWEAK and TNF-α have been shown to mediate pathological responses through inter-dependent or independent pathways by in vitro, the potential interplay of these pathways was investigated in a mouse colitis model. Acute colitis was induced by rectal injection of trinitrobenzene sulfonic acid (TNBS), with administration of control IgG, TNF receptor (TNFR)-Ig chimeric protein, anti-TWEAK monoclonal antibody, or the combination of TNFR-Ig and anti-TWEAK antibody. On day 4, disease severity was evaluated and gene expression profiling was analyzed using whole colon tissue. NF-κB activation was investigated with Western blot. Levels of transcript of TWEAK, Fn14 and NF-κB-related molecules were measured in purified colon epithelial cells (ECs). As a result, activation of the canonical (p50/RelA), but not noncanonical (p100/RelB)-mediated pathway was the hallmark of inflammatory responses in this model. Inflammation induced upregulation of Fn14 only in ECs but not in other cell types. Combination treatment of TNFR-Ig and anti-TWEAK antibody synergistically reduced disease severity in comparison with the control antibody or single agent treatment. Gene expression profile of the colon indicated downregulation of canonical NF-κB pathway with combination treatment. In conclusion, synergistic activation of canonical NF-κB by TWEAK and TNF-α is critical for the induction of inflammatory tissue damage in acute inflammation.
机译：肿瘤坏死因子（TNF）-α是各种炎症条件下的主要效应器。 TNF样的凋亡微弱诱导剂（TWEAK）是TNF超家族的成员，该家族通过其受体FGF诱导分子14（Fn14）促进炎性组织损伤。由于已显示TWEAK和TNF-α在体外均通过相互依赖或独立的途径介导病理反应，因此在小鼠结肠炎模型中研究了这些途径的潜在相互作用。直肠注射三硝基苯磺酸（TNBS），同时给予对照IgG，TNF受体（TNFR）-Ig嵌合蛋白，抗TWEAK单克隆抗体或TNFR-Ig和抗TWEAK抗体的组合，可诱发急性结肠炎。在第4天，评估疾病的严重程度，并使用整个结肠组织分析基因表达谱。用蛋白质印迹研究了NF-κB的活化。在纯化的结肠上皮细胞（EC）中测量TWEAK，Fn14和NF-κB相关分子的转录水平。结果，在该模型中，经典（p50 / RelA）介导的途径而不是非经典（p100 / RelB）介导的途径的激活是炎症反应的标志。炎症仅在EC中诱导Fn14的上调，而在其他细胞类型中则不。与对照抗体或单药治疗相比，TNFR-Ig和抗TWEAK抗体的联合治疗可协同降低疾病的严重程度。结肠的基因表达谱表明联合治疗下调了典型的NF-κB途径。总之，TWEAK和TNF-α对经典NF-κB的协同激活对于诱导急性炎症中的炎症组织损伤至关重要。

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