托法替尼
下调和上调
青少年皮肌炎
肌发生
医学
贾纳斯激酶
干扰素刺激基因
干扰素
皮肌炎
促炎细胞因子
基因表达
免疫学
癌症研究
骨骼肌
基因
内分泌学
生物
内科学
遗传学
细胞因子
炎症
类风湿性关节炎
免疫系统
先天免疫系统
作者
Lauren T Covert,Joseph A. Prinz,Devjanee Swain-Lenz,Jeffrey Dvergsten,George A. Truskey
出处
期刊:Rheumatology
[Oxford University Press]
日期:2024-02-05
被引量:1
标识
DOI:10.1093/rheumatology/keae082
摘要
Abstract Objective To better understand the pathogenesis of juvenile dermatomyositis (JDM), we examined the effect of the cytokines type I interferons (IFN I) and JAK inhibitor drugs (JAKi) on gene expression in bioengineered pediatric skeletal muscle. Methods Myoblasts from three healthy pediatric donors were used to create three-dimensional skeletal muscle units termed myobundles. Myobundles were treated with IFN I, either IFNα or IFNβ. A subset of IFNβ-exposed myobundles was treated with JAKi tofacitinib or baricitinib. RNA sequencing analysis was performed on all myobundles. Results Seventy-six myobundles were analysed. Principal component analysis showed donor-specific clusters of gene expression across IFNα and IFNβ-exposed myobundles in a dose-dependent manner. Both cytokines upregulated interferon response and proinflammatory genes; however, IFNβ led to more significant upregulation. Key downregulated pathways involved oxidative phosphorylation, fatty acid metabolism and myogenesis genes. Addition of tofacitinib or baricitinib moderated the gene expression induced by IFNβ, with partial reversal of upregulated inflammatory and downregulated myogenesis pathways. Baricitinib altered genetic profiles more than tofacitinib. Conclusion IFNβ leads to more pro-inflammatory gene upregulation than IFNα, correlating to greater decrease in contractile protein gene expression and reduced contractile force. JAK inhibitors, baricitinib more so than tofacitinib, partially reverse IFN I-induced genetic changes. Increased IFN I exposure in healthy bioengineered skeletal muscle leads to IFN-inducible gene expression, inflammatory pathway enrichment, and myogenesis gene downregulation, consistent with what is observed in JDM.
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