Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029, Korea.
Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 05029, Korea.
Molecules. 2022 Jun 30;27(13):4205. doi: 10.3390/molecules27134205.
The circadian clock system is closely associated with inflammatory responses. Dysregulation of the circadian clock genes in the skin impairs the skin barrier function and affects the pathophysiology of atopic dermatitis. Interleukin 4 (IL-4) is a proinflammatory cytokine derived from T-helper type 2 cells; it plays a critical role in the pathogenesis of atopic dermatitis. Agerarin (6,7-dimethoxy-2,2-dimethyl-2-chromene) is a natural JAK1/2/3 inhibitor isolated from that has a protective effect on the epidermal skin barrier. However, it remains unclear whether agerarin affects the circadian clock system. The aim of this study is to investigate the effect of agerarin on IL-4-induced gene expression in human keratinocytes through reverse transcription (RT)-PCR, quantitative real-time PCR (qPCR), immunoblotting, immunofluorescence microscopic analysis, and real-time bioluminescence analysis. We found that agerarin reduced IL-4-induced mRNA expression by suppressing the JAK-STAT3 pathway. In addition, real-time bioluminescence analysis in PER2:luc2p promoter-reporter cells revealed that agerarin restored the oscillatory rhythmicity of promoter activity altered by IL-4. These findings suggest that agerarin may be useful as a cosmeceutical agent against inflammatory skin conditions associated with disrupted circadian rhythms, such as atopic dermatitis.
生物钟系统与炎症反应密切相关。皮肤中生物钟基因的失调会损害皮肤屏障功能，并影响特应性皮炎的病理生理学。白细胞介素 4（IL-4）是一种源自辅助性 T 细胞 2 型（Th2 细胞）的促炎细胞因子；它在特应性皮炎的发病机制中起关键作用。agerarin（6,7-二甲氧基-2,2-二甲基-2-色烯）是一种从 中分离出的天然 JAK1/2/3 抑制剂，对表皮皮肤屏障具有保护作用。然而，agerarin 是否影响生物钟系统尚不清楚。本研究旨在通过逆转录（RT）-PCR、实时定量 PCR（qPCR）、免疫印迹、免疫荧光显微镜分析和实时生物发光分析，研究 agerarin 对人角质形成细胞中 IL-4 诱导的 基因表达的影响。我们发现 agerarin 通过抑制 JAK-STAT3 通路来减少 IL-4 诱导的 mRNA 表达。此外，在 PER2:luc2p 启动子报告细胞中的实时生物发光分析表明，agerarin 恢复了由 IL-4 改变的 启动子活性的振荡节律性。这些发现表明，agerarin 可用作治疗与生物钟紊乱相关的炎症性皮肤疾病的化妆品，如特应性皮炎。
