Interleukin-1 receptor-associated kinase 1/4 (IRAK1/4) is the main kinase of the Toll-like receptor (TLR)-mediated pathway, considered a new target for treating inflammatory diseases. Studies showed a significant correlation between TLRs and inflammatory responses in ulcerative colitis (UC). Therefore, in this study, after inducing experimental colitis in mice with 3% dextran sulfate sodium (DSS), different concentrations of IRAK1/4 inhibitors were administered intraperitoneally. Then, the disease activity index was assessed, including the degree of pathological damage, by HE staining. Subsequently, while western blotting detected the TLR4/NF-κB pathway and intestinal barrier protein expression (Zonula-1, Occludin, Claudin-1, JAM-A), real-time polymerase chain reaction (RT-PCR) detected the mRNA expression levels of IRAK1/4 and mucin1/2. Furthermore, the expression levels of Zonula-1 and occludin were detected by immunofluorescence, including the plasma FITC-dextran 4000 concentration, to evaluate intestinal barrier permeability. However, ELISA measured the expression of inflammatory factors to reflect intestinal inflammation in mice. Investigations showed that the IRAK 1/4 inhibitor significantly reduced clinical symptoms and pathological DSS-induced colitis damage in mice and then inhibited the cytoplasmic and nuclear translocation of NF-κB p65, including the phosphorylation of IκBα and reduction in downstream inflammatory factor production. Therefore, we established that the IRAK1/4 inhibitor effectively improves colitis induced by DSS, partly by inhibiting the TLR4/NF-κB pathway, reducing inflammation, and maintaining the integrity of the colonic barrier.

中文翻译：

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抑制 IRAK 1/4 通过抑制 TLR4/NF-κB 通路和保护肠道屏障来减轻结肠炎。

白介素 1 受体相关激酶 1/4 (IRAK1/4) 是 Toll 样受体 (TLR) 介导通路的主要激酶，被认为是治疗炎症性疾病的新靶点。研究表明 TLR 与溃疡性结肠炎 (UC) 中的炎症反应之间存在显着相关性。因此，在这项研究中，在用 3% 葡聚糖硫酸钠 (DSS) 诱导小鼠实验性结肠炎后，腹膜内给予不同浓度的 IRAK1/4 抑制剂。然后，通过HE染色评估疾病活动指数，包括病理损伤程度。随后，Western blotting 检测 TLR4/NF-κB 通路和肠屏障蛋白表达（Zonula-1、Occludin、Claudin-1、JAM-A），实时聚合酶链反应（RT-PCR）检测 mRNA 表达水平IRAK1/4 和粘蛋白 1/2。此外，通过免疫荧光检测 Zonula-1 和 occludin 的表达水平，包括血浆 FITC-dextran 4000 浓度，以评估肠屏障通透性。然而，ELISA 测量炎症因子的表达以反映小鼠的肠道炎症。研究表明，IRAK 1/4 抑制剂可显着减轻小鼠的临床症状和病理性 DSS 诱导的结肠炎损伤，然后抑制 NF-κB p65 的细胞质和核转位，包括 IκBα 的磷酸化和下游炎症因子产生的减少。因此，我们确定 IRAK1/4 抑制剂有效改善 DSS 诱导的结肠炎，部分是通过抑制 TLR4/NF-κB 通路、减少炎症和维持结肠屏障的完整性。免疫荧光检测Zonula-1和occludin的表达水平，包括血浆FITC-dextran 4000浓度，评价肠屏障通透性。然而，ELISA 测量炎症因子的表达以反映小鼠的肠道炎症。研究表明，IRAK 1/4 抑制剂可显着减轻小鼠的临床症状和病理性 DSS 诱导的结肠炎损伤，然后抑制 NF-κB p65 的细胞质和核转位，包括 IκBα 的磷酸化和下游炎症因子产生的减少。因此，我们确定 IRAK1/4 抑制剂有效改善 DSS 诱导的结肠炎，部分是通过抑制 TLR4/NF-κB 通路、减少炎症和维持结肠屏障的完整性。免疫荧光检测Zonula-1和occludin的表达水平，包括血浆FITC-dextran 4000浓度，评价肠屏障通透性。然而，ELISA 测量炎症因子的表达以反映小鼠的肠道炎症。研究表明，IRAK 1/4 抑制剂可显着减轻小鼠的临床症状和病理性 DSS 诱导的结肠炎损伤，然后抑制 NF-κB p65 的细胞质和核转位，包括 IκBα 的磷酸化和下游炎症因子产生的减少。因此，我们确定 IRAK1/4 抑制剂有效改善 DSS 诱导的结肠炎，部分是通过抑制 TLR4/NF-κB 通路、减少炎症和维持结肠屏障的完整性。