MicroRNA-122 protects against interferon-α-induced hepatic inflammatory response via the Janus kinase-signal transducer and activator of transcription pathway.

IF 1.3 4区 医学 Q4 ENDOCRINOLOGY & METABOLISM
Fanwei Liu, Bowen Liu, Shanshan Xu, Yinhua Ni, Xiaoli Liu
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Abstract

Significant overlap in the epidemiology and coinfection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) has been identified, which accelerates the development of severe liver cirrhosis and hepatocellular carcinoma worldwide. Interferon-α (IFN-α), a cytokine with antiviral properties, exerts profound physiological effects on innate immunity by regulating interferon-stimulated genes (ISGs) within cells. However, the underlying mechanism of IFN-α in hepatic inflammation remains to be fully elucidated. Here, we utilized LO2 cells treated with the recombinant IFN-α protein and conducted microRNA (miR) sequencing. MiR-122-3p and miR-122-5p_R+1 were the most enriched miRNAs involved in the pathogenesis of IFN-α-induced inflammatory responses and were significantly downregulated by IFN-α treatment. Furthermore, we identified interferon induced protein with tetratricopeptide repeats 1 (IFIT1) as a potential target gene of miR-122. IFN-α markedly increased the expression of proinflammatory cytokines and fibrogenic genes but decreased the mRNA expression of ISGs. Additionally, IFN-α significantly activated the NF-κB p-p65, MAPK p-p38, and Jak/STAT pathways to trigger inflammation. Importantly, supplementation with a miR-122 mimic significantly alleviated IFN-α-induced inflammation and induced IFIT1 expression in LO2 cells. Conversely, the suppression of miR-122 markedly exacerbated the inflammatory response triggered by IFN-α. Furthermore, silencing IFIT1 via an siRNA elicited an inflammatory response, whereas IFIT1 overexpression ameliorated hepatic inflammation and fibrosis in a manner comparable to that induced by IFN-α treatment. Taken together, our findings suggest that miR-122 and its target, IFIT1, reciprocally regulate the inflammatory response associated with IFN through the Jak/STAT pathway.

MicroRNA-122 通过 Janus 激酶-信号转导和转录激活因子通路防止干扰素-α 诱导的肝脏炎症反应。
已发现慢性乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)的流行病学和合并感染有明显的重叠,这加速了全球严重肝硬化和肝细胞癌的发展。干扰素-α(IFN-α)是一种具有抗病毒特性的细胞因子,它通过调节细胞内的干扰素刺激基因(ISGs)对先天性免疫产生深远的生理影响。然而,IFN-α在肝脏炎症中的潜在机制仍有待全面阐明。在此,我们利用重组 IFN-α 蛋白处理过的 LO2 细胞,进行了微RNA(miR)测序。MiR-122-3p 和 miR-122-5p_R+1 是参与 IFN-α 诱导的炎症反应发病机制的最丰富的 miRNA,并在 IFN-α 处理后显著下调。此外,我们还发现具有四重肽重复序列的干扰素诱导蛋白 1(IFIT1)是 miR-122 的潜在靶基因。IFN-α 显著增加了促炎细胞因子和纤维化基因的表达,但降低了 ISGs 的 mRNA 表达。此外,IFN-α 还能显著激活 NF-κB p-p65、MAPK p-p38 和 Jak/STAT 通路,从而引发炎症。重要的是,补充 miR-122 模拟物能明显缓解 IFN-α 诱导的炎症,并诱导 LO2 细胞中 IFIT1 的表达。相反,抑制 miR-122 会明显加剧 IFN-α 引发的炎症反应。此外,通过 siRNA 沉默 IFIT1 会引起炎症反应,而过表达 IFIT1 则会改善肝脏炎症和纤维化,其方式与 IFN-α 治疗诱导的方式类似。综上所述,我们的研究结果表明,miR-122 及其靶标 IFIT1 通过 Jak/STAT 通路相互调节与 IFN 相关的炎症反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Endocrine journal
Endocrine journal 医学-内分泌学与代谢
CiteScore
4.30
自引率
5.00%
发文量
224
审稿时长
1.5 months
期刊介绍: Endocrine Journal is an open access, peer-reviewed online journal with a long history. This journal publishes peer-reviewed research articles in multifaceted fields of basic, translational and clinical endocrinology. Endocrine Journal provides a chance to exchange your ideas, concepts and scientific observations in any area of recent endocrinology. Manuscripts may be submitted as Original Articles, Notes, Rapid Communications or Review Articles. We have a rapid reviewing and editorial decision system and pay a special attention to our quick, truly scientific and frequently-citable publication. Please go through the link for author guideline.
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