Department of Dermatology, Fukuoka University Faculty of Medicine, Fukuoka, Japan.
Department of Pharmaceutics, Fukuoka University Faculty of Pharmaceutical Sciences, Fukuoka, Japan.
J Dermatol. 2020 Apr;47(4):390-396. doi: 10.1111/1346-8138.15250. Epub 2020 Feb 5.
Immunotherapies targeting interleukin (IL)-17 greatly improve plaque psoriasis. Most previous studies on IL-17 focused on the T-helper (Th)17 immune response, but investigation of the effects of IL-17A on psoriatic epidermal structure are limited. Using an in vitro 3-D human epidermis model, we investigated the effects of IL-17A and IL-17C on morphological changes and gene expression. IL-17A directly suppressed the formation of the granular layer, whereas IL-17C did not. IL-17A significantly downregulated the gene expression of profilaggrin (FLG), which is a major component of keratohyalin granules in the granular layer. Global gene expression analysis of this 3-D epidermis model showed that both IL-17A and IL-17C upregulated S100A7A and type 1 interferon-related genes including MX1, IFI44L, XAF1 and IFIT1. However, only IL-17A directly downregulated keratinocyte differentiation-related and cornified envelope-related genes including FLG, LOR, C1ORF68, LCE1E, LCE1B, KRT10, CST6 and RPTN. In conclusion, IL-17A, a systemic inflammatory cytokine, affected keratinization in our 3-D epidermis model. In contrast, IL-17C, a locally produced cytokine, did not have strong effects on keratinization. Targeting IL-17A does not only reduce inflammation but it may also directly affect epidermal differentiation in psoriasis.
针对白细胞介素 (IL)-17 的免疫疗法极大地改善了斑块状银屑病。大多数之前关于 IL-17 的研究都集中在辅助性 T 细胞 (Th)17 免疫反应上，但对 IL-17A 对银屑病表皮结构的影响的研究有限。我们使用体外 3-D 人表皮模型研究了 IL-17A 和 IL-17C 对形态变化和基因表达的影响。IL-17A 直接抑制颗粒层的形成，而 IL-17C 则没有。IL-17A 显著下调了颗粒层中角蛋白丝聚合蛋白 (FLG)的基因表达，FLG 是角蛋白丝聚合蛋白的主要成分。对该 3-D 表皮模型的全基因表达分析表明，IL-17A 和 IL-17C 均上调了 S100A7A 和包括 MX1、IFI44L、XAF1 和 IFIT1 在内的 I 型干扰素相关基因。然而，只有 IL-17A 直接下调了包括 FLG、LOR、C1ORF68、LCE1E、LCE1B、KRT10、CST6 和 RPTN 在内的角蛋白细胞分化相关和角质层相关基因。总之，系统性炎症细胞因子 IL-17A 影响了我们 3-D 表皮模型中的角质化。相比之下，局部产生的细胞因子 IL-17C 对角质化没有强烈影响。靶向 IL-17A 不仅可以减轻炎症，还可能直接影响银屑病中的表皮分化。
