He Zhi, Feng Ya-Dong, Zhang Yue-Xin, Gao Xun, Liu Jing-Jing, Liu Shuang, Wu Guo-Qiu
Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, 87 Ding Jiaqiao, Nanjing 210009, China.
Department of Gastroenterology, Zhongda Hospital, Southeast University, 87 Ding Jiaqiao, Nanjing 210009, China.
Cell Signal. 2025 Jun 18;134:111932. doi: 10.1016/j.cellsig.2025.111932.
BACKGROUND: Interleukin-10 (IL-10), an anti-inflammatory cytokine, has shown therapeutic effect on autoimmune diseases, yet its effects on UC remain unclear. This study aims to investigate whether the administration of IL-10 can suppress disease flares in ulcerative colitis (UC). METHODS: A UC model was established in mice using dextran sulfate sodium (DSS) to evaluate the therapeutic effect of IL-10. LPS-stimulated Caco-2 cells were utilized to explore the underlying molecular mechanisms, focusing on apoptosis, inflammation, and oxidative stress. RESULTS: IL-10 administration significantly alleviated clinical symptoms in DSS-induced colitis, including promoting body weight recovery, increasing colon length, and reducing disease activity index scores. IL-10 repaired the intestinal mucosal barrier by inhibiting apoptosis of intestinal epithelial cells, downregulating pro-inflammatory cytokines (IL-6, Interferon-γ, and IL-1β), and modulating oxidative stress markers, such as malondialdehyde (MDA) and superoxide dismutase (SOD). In LPS-stimulated Caco-2 cells, IL-10 protected against apoptosis, oxidative stress, and inflammation. Bioinformatics analysis of control and IL-10 knockout mice showed a significant upregulation of Interferon-Stimulated Gene 15 (ISG15) after IL-10 knockout. In contrast, ISG15 expression was downregulated in the LPS + IL-10 group but upregulated in LPS-stimulated Caco-2 cells. These results suggest that ISG15 is a target gene of IL-10 and plays a role in autophagy regulation. Furthermore, IL-10 enhanced autophagy by increasing the protein expression of ATG7, and the LC3-II/LC3-I ratio, thereby reducing apoptosis and oxidative stress in Caco-2 cells. Autophagy inhibition with 3-Methyladenine or overexpression of ISG15 diminished IL-10's protective effects. CONCLUSION: This study demonstrates that IL-10 administration inhibits the progression of UC by activating autophagy and modulating ISG15 expression. In the future, targeted delivery of IL-10 to the intestinal lamina propria may enhance therapeutic efficacy while minimizing systemic side effects.
背景：白细胞介素 - 10（IL - 10）是一种抗炎细胞因子，已显示出对自身免疫性疾病的治疗作用，但其对溃疡性结肠炎（UC）的影响仍不清楚。本研究旨在探讨给予IL - 10是否能抑制溃疡性结肠炎（UC）的疾病发作。 方法：使用葡聚糖硫酸钠（DSS）在小鼠中建立UC模型，以评估IL - 10的治疗效果。利用脂多糖（LPS）刺激的Caco - 2细胞来探索潜在的分子机制，重点关注细胞凋亡、炎症和氧化应激。 结果：给予IL - 10可显著减轻DSS诱导的结肠炎的临床症状，包括促进体重恢复、增加结肠长度和降低疾病活动指数评分。IL - 10通过抑制肠上皮细胞凋亡、下调促炎细胞因子（IL - 6、干扰素 - γ和IL - 1β）以及调节氧化应激标志物，如丙二醛（MDA）和超氧化物歧化酶（SOD），修复肠道黏膜屏障。在LPS刺激的Caco - 2细胞中，IL - 10可防止细胞凋亡、氧化应激和炎症。对对照小鼠和IL - 10基因敲除小鼠的生物信息学分析显示，IL - 10基因敲除后干扰素刺激基因15（ISG15）显著上调。相反，在LPS + IL - 10组中ISG15表达下调，但在LPS刺激的Caco - 2细胞中上调。这些结果表明ISG15是IL - 10的靶基因，并在自噬调节中发挥作用。此外，IL - 10通过增加ATG7的蛋白表达和LC3 - II/LC3 - I比值来增强自噬，从而减少Caco - 2细胞中的细胞凋亡和氧化应激。用3 - 甲基腺嘌呤抑制自噬或过表达ISG15会减弱IL - 10的保护作用。 结论：本研究表明，给予IL - 10通过激活自噬和调节ISG15表达来抑制UC的进展。未来，将IL - 10靶向递送至肠固有层可能会提高治疗效果，同时将全身副作用降至最低。
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