Ádám Dorottya, Arany József, Tóth Kinga Fanni, Póliska Szilárd, Váradi Judit, Kolozsi Péter, Tóth Dezső, Niehues Hanna, van den Bogaard Ellen H, Soeberdt Michael, Abels Christoph, Oláh Attila
Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
Arch Dermatol Res. 2025 Jan 18;317(1):277. doi: 10.1007/s00403-024-03711-9.
We have recently shown that fluoxetine (FX) suppressed polyinosinic-polycytidylic acid-induced inflammatory response and endothelin release in human epidermal keratinocytes, via the indirect inhibition of the phosphoinositide 3-kinase (PI3K)-pathway. Because PI3K-signaling is a positive regulator of the proliferation, in the current, highly focused follow-up study, we assessed the effects of FX (14 µM) on the proliferation and differentiation of human epidermal keratinocytes. We found that FX exerted anti-proliferative actions in 2D cultures (HaCaT and primary human epidermal keratinocytes [NHEKs]; 48- and 72-h; CyQUANT-assay) as well as in 3D reconstructed epidermal equivalents (48-h; Ki-67 immunohistochemistry). Importantly, FX did not influence epidermal thickness (hematoxylin-eosin staining), and it did not have a major impact on the differentiation-associated alteration of the gene expression pattern (24-h treatments; RNA-Seq). Moreover, neither keratin (K)-1, nor K10 expression was altered by FX in NHEKs (RT-qPCR) or in 3D epidermal equivalents (semi-quantitative immunohistomorphometry). FX did not influence differentiation-induced up-regulation of occludin (RT-qPCR; NHEKs), and did not alter differentiation-associated barrier forming capacity of epidermal keratinocytes (electrical impedance; Lucifer Yellow penetration assay). Our data indicate that, besides the previously reported combined anti-inflammatory and putative anti-pruritic effects, FX may also suppress proliferation of human epidermal keratinocytes without impairing their differentiation and barrier-forming capacity.
我们最近发现，氟西汀（FX）可通过间接抑制磷酸肌醇3激酶（PI3K）信号通路，抑制人表皮角质形成细胞中多聚肌苷酸-多聚胞苷酸诱导的炎症反应和内皮素释放。由于PI3K信号是增殖的正调节因子，在当前这项高度聚焦的后续研究中，我们评估了FX（14µM）对人表皮角质形成细胞增殖和分化的影响。我们发现，FX在二维培养（HaCaT和原代人表皮角质形成细胞[NHEKs]；48小时和72小时；CyQUANT检测）以及三维重建表皮等效物（48小时；Ki-67免疫组化）中均发挥抗增殖作用。重要的是，FX不影响表皮厚度（苏木精-伊红染色），且对基因表达模式的分化相关改变没有重大影响（24小时处理；RNA测序）。此外，FX在NHEKs（RT-qPCR）或三维表皮等效物（半定量免疫组织形态计量学）中均未改变角蛋白（K）-1或K10的表达。FX不影响分化诱导的闭合蛋白上调（RT-qPCR；NHEKs），也不改变表皮角质形成细胞的分化相关屏障形成能力（电阻抗；荧光素黄渗透试验）。我们的数据表明，除了先前报道的抗炎和假定的止痒联合作用外，FX还可能抑制人表皮角质形成细胞的增殖，而不损害其分化和屏障形成能力。
