Department of Surgery, Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang, People’s Republic of China.
Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang, People’s Republic of China.
Aging (Albany NY). 2023 May 20;15(10):4363-4373. doi: 10.18632/aging.204739.
This study was aimed at investigating the expression and role of proprotein convertase subtilisin/kexin type (PCSK6) in inflammatory bowel disease (IBD). DSS induced mouse colitis and mucosal barrier injury, down-regulation of TJ proteins, improvement of permeability, and increases of the proportions of Th1 and M1 macrophages. After PCSK6 knockdown, the colitis in KO mice was improved relative to WT mice, the TJ protein levels increased, and the proportions of Th1 and M1 macrophages decreased. STAT1 inhibitor treatment also inhibited chronic colitis in mice. As revealed by experiments, PCSK6 overexpression promoted the transformation of Th0 into Th1, while PCSK6 silencing suppressed the transfection. COPI assay results revealed the presence of targeted binding relation between PCSK6 and STAT1. PCSK6 binds to STAT1 to promote STAT1 phosphorylation and regulate Th1 cell differentiation, thus promoting the M1 polarization of macrophages and aggravating colitis progression. PCSK6 is promising as the new target for the treatment of colitis.
本研究旨在探讨前蛋白转化酶枯草溶菌素/克氏蛋白酶 6（PCSK6）在炎症性肠病（IBD）中的表达和作用。DSS 诱导的小鼠结肠炎和黏膜屏障损伤，TJ 蛋白下调，通透性增加，Th1 和 M1 巨噬细胞比例增加。PCSK6 敲低后，KO 小鼠的结肠炎较 WT 小鼠改善，TJ 蛋白水平增加，Th1 和 M1 巨噬细胞比例减少。STAT1 抑制剂治疗也抑制了小鼠的慢性结肠炎。实验表明，PCSK6 过表达促进 Th0 向 Th1 的转化，而 PCSK6 沉默抑制转染。COPI 实验结果显示 PCSK6 和 STAT1 之间存在靶向结合关系。PCSK6 与 STAT1 结合，促进 STAT1 磷酸化，调节 Th1 细胞分化，从而促进巨噬细胞 M1 极化，加重结肠炎进展。PCSK6 有望成为治疗结肠炎的新靶点。
