Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; Genomic and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):113086. doi: 10.1016/j.intimp.2024.113086. Epub 2024 Sep 12.
Interleukin (IL)-37, a unique member of the IL-1 family, is known for its anti-inflammatory properties. However, its effects on immune-mediated liver diseases, such as primary biliary cholangitis (PBC) and acute immune-mediated hepatitis, remain unclear. Using mouse models of autoimmune cholangitis and hepatitis induced by 2-OA-OVA and concanavalin A (Con A) respectively, we introduced the human IL-37 gene via a liver-preferred adeno-associated virus vector (AAV-IL-37) to mice, as mice lack endogenous IL-37. Our findings reveal that IL-37 did not affect autoimmune cholangitis. Surprisingly, IL-37 exacerbated inflammation in Con A-induced hepatitis rather than mitigating it. Mechanistic insights suggest that this exacerbation involves the interferon (IFN)-γ pathway, supported by elevated serum IFN-γ levels in AAV-IL-37-treated Con A mice. Specifically, IL-37 heightened the number of hepatic NK and NKT cells, increased the production of the NK cell chemoattractant CCL5, and elevated the frequency of hepatic NK and NKT cells expressing IFN-γ. Moreover, IL-37 enhanced IFN-γ secretion from NK cells when combined with other proinflammatory cytokines, highlighting its synergistic effect in promoting IFN-γ production. These unexpected outcomes underscore a novel role for IL-37 in exacerbating liver inflammation during immune-mediated liver diseases, implicating its influence on NK cells and the production of IFN-γ by these cells.
白细胞介素 (IL)-37 是 IL-1 家族的独特成员，以其抗炎特性而闻名。然而，其对原发性胆汁性胆管炎 (PBC) 和急性免疫介导性肝炎等免疫介导性肝疾病的影响尚不清楚。我们使用由 2-OA-OVA 和伴刀豆球蛋白 A (Con A) 分别诱导的自身免疫性胆管炎和肝炎的小鼠模型，通过肝脏偏好性腺相关病毒载体 (AAV-IL-37) 将人 IL-37 基因导入小鼠，因为小鼠缺乏内源性 IL-37。我们的研究结果表明，IL-37 不会影响自身免疫性胆管炎。令人惊讶的是，IL-37 加剧了 Con A 诱导的肝炎中的炎症，而不是减轻炎症。机制研究表明，这种加剧涉及干扰素 (IFN)-γ 途径，AAV-IL-37 治疗的 Con A 小鼠血清 IFN-γ 水平升高支持这一观点。具体而言，IL-37 增加了肝 NK 和 NKT 细胞的数量，增加了 NK 细胞趋化因子 CCL5 的产生，并增加了表达 IFN-γ 的肝 NK 和 NKT 细胞的频率。此外，IL-37 增强了 NK 细胞与其他促炎细胞因子联合时 IFN-γ 的分泌，突出了其在促进 IFN-γ 产生中的协同作用。这些意外的结果突显了 IL-37 在免疫介导性肝疾病中加剧肝炎症的新作用，暗示其对 NK 细胞及其产生 IFN-γ 的影响。
