Department of Medicine, Dermatology and Venereology Unit, Karolinska Institutet, 171 76 Stockholm, Sweden.
Acta Derm Venereol. 2018 Aug 29;98(8):772-775. doi: 10.2340/00015555-2960.
Tofacitinib is a Janus kinase (JAK) inhibitor, which has shown efficacy in treating psoriasis. The mode of action of tofacitinib is not completely understood but it has been thought to be mediated by the inhibition of CD4+ T-cell activation. Here, we investigated whether the molecular targets of tofacitinib are expressed in keratinocytes, and whether tofacitinib can modulate the activity of the JAK/Signal Transducer and Activators of Transcription (STAT)-pathway in keratinocytes. Transcriptomic profiling of human keratinocytes treated with IL-22 in combination with tofacitinib revealed that tofacitinib could prevent the majority of IL-22-mediated gene expression changes. Pathway analysis of tofacitinib-regulated genes in keratinocytes revealed enrichment of genes involved in the JAK/STAT signalling pathway. Quantitative real-time-PCR confirmed the upregulation of S100A7 and downregulation of EGR1 expression by IL-22, which was prevented by tofacitinib pre-treatment. These results indicate a direct effect of tofacinitib on keratinocytes, which can have relevance for systemic as well as for topical treatment of psoriasis with tofacitinib.
托法替尼是一种 Janus 激酶（JAK）抑制剂，已被证明在治疗银屑病方面有效。托法替尼的作用机制尚不完全清楚，但据认为是通过抑制 CD4+T 细胞的激活来介导的。在这里，我们研究了托法替尼的分子靶标是否在角质形成细胞中表达，以及托法替尼是否可以调节角质形成细胞中的 JAK/信号转导和转录激活因子（STAT）-通路的活性。用 IL-22 联合托法替尼处理的人角质形成细胞的转录组学分析表明，托法替尼可以阻止大多数 IL-22 介导的基因表达变化。对角质形成细胞中托法替尼调节基因的通路分析显示，JAK/STAT 信号通路相关基因富集。定量实时 PCR 证实了 IL-22 上调 S100A7 和下调 EGR1 的表达，而托法替尼预处理可防止这种表达。这些结果表明托法替尼对角质形成细胞有直接作用，这可能与全身性以及局部使用托法替尼治疗银屑病有关。
