Wang An-Jiang, Yang Zhonghan, Grinchuk Viktoriya, Smith Allen, Qin Bolin, Lu Nonghua, Wang Duan, Wang Hongbing, Ramalingam Thirumalai R, Wynn Thomas A, Urban Joseph F, Shea-Donohue Terez, Zhao Aiping
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Gastroenterology and Hepatology, First Affiliated Hospital of Nanchang University, Nanchang 330006, China;
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510080, China;
J Immunol. 2015 Nov 15;195(10):4771-80. doi: 10.4049/jimmunol.1500337. Epub 2015 Sep 30.
IL-25 or IL-17E is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet (LD) proteins, were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased LD proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD-fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively activated Kupffer cells/macrophages, and decreased expression of LD proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in downregulation of LD proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, whereas exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies.
白细胞介素-25（IL-25）或IL-17E是白细胞介素-17细胞因子家族的成员，具有免疫调节活性。IL-25在维持脂质代谢稳态中的作用尚不清楚。我们研究了外源性IL-25或IL-25缺乏对肝脏脂质积累的影响。在患者肝脏的石蜡包埋组织切片或小鼠肝脏中检测IL-25的表达。通过喂食高脂饮食（HFD）诱导小鼠脂肪变性模型。分析了脂肪变性程度以及细胞因子、脂质代谢途径关键酶、库普弗细胞/巨噬细胞标志物和脂滴（LD）蛋白的表达。我们的结果表明，小鼠肝脏脂肪变性伴随着肝脏中LD蛋白增加，但IL-25减少。在脂肪肝患者中也观察到肝脏IL-25减少。给喂食HFD的野生型小鼠施用IL-25可显著改善肝脏脂肪变性。这种作用与IL-13表达增加、交替活化的库普弗细胞/巨噬细胞的发育以及肝脏中LD蛋白表达减少有关。相比之下，给缺乏STAT6或IL-13的喂食HFD的小鼠施用IL-25没有效果。此外，用IL-13而非IL-25刺激原代肝细胞会导致LD蛋白下调。最后，缺乏IL-25的小鼠在喂食HFD时肝脏脂质积累加剧。这些数据表明，IL-25表达失调导致脂质积累，而外源性IL-25通过IL-13激活STAT6预防肝脏脂肪变性。IL-25和IL-13是肝脏脂肪变性及相关病变的潜在治疗药物。
