Dong Xiang-Qian, Zhang Ying-Hui, Luo Juan, Li Mao-Juan, Ma Lan-Qing, Qi Ya-Ting, Miao Ying-Lei
Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China.
Department of Gastroenterology, Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China.
World J Gastroenterol. 2025 Feb 14;31(6):102070. doi: 10.3748/wjg.v31.i6.102070.
External factors in ulcerative colitis (UC) exacerbate colonic epithelial permeability and inflammatory responses. Keratin 1 (KRT1) is crucial in regulating these alterations, but its specific role in the progression of UC remains to be fully elucidated.
To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC.
A KRT1 antibody concentration gradient test, along with a dextran sulfate sodium (DSS)-induced animal model, was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system (KKS) and the cleavage of bradykinin (BK)/high molecular weight kininogen (HK) in UC.
Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation, induced apoptosis, reduced HK expression, and increased BK expression. It further downregulated intestinal barrier proteins, including occludin, zonula occludens-1, and claudin, and negatively impacted the coagulation factor XII. These changes led to enhanced activation of BK and HK cleavage, thereby intensifying KKS-mediated inflammation in UC. In the DSS-induced mouse model, administration of KRT1 antibody mitigated colonic injury, increased colon length, alleviated weight loss, and suppressed inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α. It also facilitated repair of the intestinal barrier, reducing DSS-induced injury.
KRT1 inhibits BK expression, suppresses inflammatory cytokines, and enhances markers of intestinal barrier function, thus ameliorating colonic damage and maintaining barrier integrity. KRT1 is a viable therapeutic target for UC.
溃疡性结肠炎（UC）中的外部因素会加剧结肠上皮通透性和炎症反应。角蛋白1（KRT1）在调节这些改变中起关键作用，但其在UC进展中的具体作用仍有待充分阐明。
探讨KRT1在UC中调节结肠上皮通透性和炎症的作用及机制。
进行KRT1抗体浓度梯度试验，并采用葡聚糖硫酸钠（DSS）诱导的动物模型，以研究KRT1在UC中调节激肽释放酶激肽系统（KKS）激活以及缓激肽（BK）/高分子量激肽原（HK）裂解的作用。
在Caco-2细胞中用KRT1抗体处理可抑制细胞增殖、诱导细胞凋亡、降低HK表达并增加BK表达。它还进一步下调包括闭合蛋白、紧密连接蛋白1和claudin在内的肠道屏障蛋白，并对凝血因子XII产生负面影响。这些变化导致BK和HK裂解的激活增强，从而加剧UC中KKS介导的炎症。在DSS诱导的小鼠模型中，给予KRT1抗体可减轻结肠损伤、增加结肠长度、减轻体重减轻，并抑制白细胞介素（IL）-1、IL-6、肿瘤坏死因子-α等炎性细胞因子。它还促进肠道屏障的修复，减少DSS诱导的损伤。
KRT1抑制BK表达，抑制炎性细胞因子，并增强肠道屏障功能标志物，从而改善结肠损伤并维持屏障完整性。KRT1是UC的一个可行治疗靶点。
