白细胞介素-1β在克罗恩病肠纤维化中通过糖代谢重编程抑制肠成纤维细胞活化的机制研究
| 作 者：林俊杰, 王璐, 孙君健, 王舒, 郭琼, 张红杰, 赵小静 |
| 单 位：江苏省人民医院 |
| 基金项目：国家自然科学基金；中国博士后科学基金 |
| 摘 要： |
| 背景：克罗恩病（CD）肠纤维化是临床治疗的难点，探究CD肠纤维化的调控机制将为寻求新的治疗靶点提供思路。目的：系统探讨白细胞介素-1β（IL-1β）在CD肠纤维化中的调控作用及其可能机制。方法：分离培养源自CD患者的原代肠成纤维细胞，予不同细胞因子处理，RT-qPCR检测双调蛋白（Areg）基因表达。基于初步实验结果选择10 ng/mL IL-1β处理肠成纤维细胞，行转录组测序和差异表达基因KEGG通路富集分析。通过细胞划痕实验、Ki-67免疫荧光染色以及胶原蛋白、肌成纤维细胞标志物检测，结合糖酵解特异性抑制剂2-脱氧-D-葡萄糖（2-DG）干预实验，评估IL-1β是否通过促进糖酵解抑制肠成纤维细胞活化和增殖。结果：IL-1β可促进CD肠成纤维细胞Areg基因表达，同时抑制Ⅰ型、Ⅵ型胶原基因表达。经IL-1β处理的肠成纤维细胞α-平滑肌肌动蛋白和波形蛋白基因表达显著下调，细胞迁移面积减小，提示细胞活化和迁移能力受抑。机制研究表明，经IL-1β处理的肠成纤维细胞差异表达基因主要富集于代谢通路；IL-1β可诱导肠成纤维细胞糖代谢重编程，上调磷酸果糖激酶-肝型、丙酮酸激酶M型等糖酵解关键酶基因表达，促进糖酵解；糖酵解特异性抑制剂2-DG可部分逆转IL-1β的抗纤维化作用。结论：本研究首次揭示了IL-1β通过糖代谢重编程抑制肠纤维化的新机制，其双重调控作用为理解炎症与纤维化的复杂关系提供了新视角，并为开发靶向代谢干预策略提供了理论依据。针对CD肠纤维化的治疗需要综合考虑IL-1β的双重作用，IL-1β诱导的糖酵解重编程可能成为新的治疗靶点。 |
| 关键词：白细胞介素1β；糖酵解；糖代谢重编程；成纤维细胞；Crohn病；肠纤维化 |
Mechanism of Interleukin-1β Inhibiting Intestinal Fibroblasts Activation Through Glucose Metabolic Reprogramming in Crohn′s Disease-associated Intestinal Fibrosis
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| Abstract: |
| Background: Intestinal fibrosis remains a major clinical challenge in Crohn′s disease (CD). Elucidating the regulatory pathways underlying CD-associated intestinal fibrosis is crucial for the identification of novel therapeutic targets. Aims: To systematically investigate the regulatory role and mechanisms of interleukin-1β (IL-1β) in CD-associated intestinal fibrosis. Methods: Primary intestinal fibroblasts were isolated from CD patients and treated with various cytokines to assess amphiregulin (Areg) gene expression by RT-qPCR. Based on preliminary results, RNA sequencing was performed on intestinal fibroblasts treated with 10 ng/mL IL-1β to identify differentially expressed genes, followed by KEGG pathway enrichment analysis. Proliferation and activation of intestinal fibroblasts were assessed through would healing assay, Ki-67 immunofluorescence, collagens and myofibroblast markers detection, and 2-deoxy-D-glucose (2-DG; a specific inhibitor of glycolysis) intervention experiment was applied to determine the role of glycolysis in IL-1β-mediated effects. Results: IL-1β significantly increased Areg gene expression while suppressing type Ⅰ and Ⅵ collagen genes in intestinal fibroblasts of CD patients. IL-1β treatment suppressed the activation and migration capabilities of intestinal fibroblasts, as evidenced by the significant downregulation of α-smooth muscle actin and vimentin gene expression and the reduction in cell migration area. Differentially expressed genes in intestinal fibroblasts treated with IL-1β were primarily enriched in metabolic pathways. Mechanistically, IL-1β induced glucose metabolic reprogramming characterized by upregulated gene expression of glycolytic enzymes (phosphofructokinase, liver type; pyruvate kinase, muscle type; etc.) and enhanced glycolysis in intestinal fibroblasts. The specific glycolysis inhibitor 2-DG partially reversed IL-1β's anti-fibrotic effects. Conclusions: This study reveals a novel mechanism whereby IL-1β suppresses intestinal fibrosis through glucose metabolic reprogramming. The dual regulatory roles of IL-1β provide new insights into the inflammation-fibrosis interplay and establish a theoretical foundation for developing metabolism-targeted therapeutic strategies. Treatment of CD-associated intestinal fibrosis should consider IL-1β's dual effects. IL-1β-induced glycolytic reprogramming might represent a potential therapeutic target. |
| Keywords: Interleukin-1beta; Glycolysis; Glucose Metabolic Reprogramming; Fibroblasts; Crohn Disease; Intestinal Fibrosis |
| 投稿时间：2025-07-14 |
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