IL-18通过激活肾小管上皮细胞中的Wnt/β-连环蛋白信号通路促进狼疮性肾炎的发展
IL-18 Promotes the Development of Lupus Nephritis by Activating the Wnt/β-Catenin Signaling Pathway in Renal Tubular Epithelial Cells.
摘要(中文译文)
本研究探讨白细胞介素-18（IL-18）在狼疮性肾炎（LN）进展中的具体作用及其分子机制，为LN的病理干预提供理论依据。研究检测了伴或不伴LN的系统性红斑狼疮（SLE）患者的IL-18水平。对MRL/lpr小鼠腹腔注射IL-18或其抑制剂，以评估肾损伤、炎症及Wnt/β-catenin通路活性。进行了体内干预实验，使用Caspase-1抑制剂（Ac-YVAD-CMK）、Wnt通路激动剂（BML-284）和抑制剂（IWR-1-endo）。体外研究采用人肾小管上皮细胞系HK-2探讨分子机制。结果显示，IL-18在SLE患者中显著升高，并在LN患者的尿液和肾组织中进一步升高。在MRL/lpr小鼠中，外源性IL-18显著加重肾损伤，表现为尿蛋白、血清肌酐、抗dsDNA抗体升高，肾小管间质炎症及活动指数增加。同时伴有IFN-γ、IL-1β、IL-6上调，IL-10下调，以及Wnt/β-catenin通路激活（β-catenin、p-GSK-3β和CK1α升高）。相反，阻断IL-18或抑制Wnt可减轻这些病理改变。值得注意的是，同时激活Wnt可逆转IL-18抑制的保护作用。体外实验中，IL-18通过激活Wnt/β-catenin信号促进HK-2细胞增殖和炎症因子分泌，这些效应可被Caspase-1抑制剂或Wnt通路抑制剂阻断。结论认为，IL-18通过激活肾小管上皮细胞中的Wnt/β-catenin信号通路并破坏促炎与抗炎细胞因子网络的平衡，从而加重肾小管间质炎症并促进LN小鼠的肾损伤。这些发现凸显了靶向IL-18信号通路治疗LN的潜力。试验注册：不适用。
Abstract
This study investigates the specific role of interleukin-18 (IL-18) in lupus nephritis (LN) progression and its molecular mechanisms to provide a theoretical basis for the pathological intervention of LN. IL-18 levels were measured from systemic lupus erythematosus (SLE) patients with or without LN. MRL/lpr mice received intraperitoneal injection of IL-18 or its inhibitor to assess renal injury, inflammation, and Wnt/β-catenin pathway activity. In-vivo intervention experiments using Caspase-1 inhibitor (Ac-YVAD-CMK), Wnt pathway agonists (BML-284), and inhibitors (IWR-1-endo) were performed. In-vitro studies were conducted in human renal tubular epithelial cell line HK-2 to investigate the molecular mechanisms. IL-18 was markedly elevated in SLE patients, and further increased in urine and renal tissue of LN. In MRL/lpr mice, exogenous IL-18 significantly exacerbated renal injury, evidenced by increased urinary protein, serum creatinine, anti-dsDNA antibodies, tubulointerstitial inflammation, and increased activity index. This was accompanied by up-regulation of IFN-γ, IL-1β, IL-6, down-regulation of IL-10, and activation of the Wnt/β-catenin pathway (increased β-catenin, p-GSK-3β, and CK1α). Conversely, IL-18 blockade or Wnt inhibition attenuated these pathological changes. Notably, the protective effects of IL-18 inhibition were reversed by simultaneous Wnt activation. In-vitro, IL-18 promoted HK-2 cell proliferation and inflammatory secretion by activating Wnt/β-catenin signaling, effects which were blocked by a Caspase-1 inhibitor or a Wnt pathway inhibitor. IL-18 activated the Wnt/β-catenin signaling pathway in renal tubular epithelial cells and disrupted the balance of pro- and anti-inflammatory cytokine networks, thereby exacerbating tubulointerstitial inflammation and promoting renal injury in LN mice. These findings highlight the therapeutic potential of targeting the IL-18 signaling pathway in LN. Trial registration: Not applicable.
如何引用
AMA
Jiashun Zeng, Yan Ting, Hong Yin, Si Yang, Lifen Xu. IL-18 Promotes the Development of Lupus Nephritis by Activating the Wnt/β-Catenin Signaling Pathway in Renal Tubular Epithelial Cells.. Inflammation. 2026; doi:10.1007/s10753-026-02569-5.
APA
Jiashun Zeng, Yan Ting, Hong Yin, Si Yang, Lifen Xu (2026). IL-18 Promotes the Development of Lupus Nephritis by Activating the Wnt/β-Catenin Signaling Pathway in Renal Tubular Epithelial Cells.. Inflammation. https://doi.org/10.1007/s10753-026-02569-5
GB/T 7714
Jiashun Zeng, Yan Ting, Hong Yin, Si Yang, Lifen Xu. IL-18 Promotes the Development of Lupus Nephritis by Activating the Wnt/β-Catenin Signaling Pathway in Renal Tubular Epithelial Cells.[J]. Inflammation, 2026 doi:10.1007/s10753-026-02569-5.
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