Sol J. Barer Laboratories, Department of Translational Development, Celgene Corporation, 181 Passaic Avenue, Summit, NJ, 07901, USA.
Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Drugs R D. 2019 Dec;19(4):329-338. doi: 10.1007/s40268-019-00284-1.
Apremilast, an oral phosphodiesterase (PDE) 4 inhibitor, has demonstrated efficacy in psoriasis, while its efficacy in atopic dermatitis (AD) was found to be modest. AD is a chronic inflammatory skin disease associated with activation of T helper (Th) 2 and Th17 immunity and a compromised epidermal barrier.
The objectives of this study were to examine the expression of PDE4 isoforms in skin from healthy subjects and AD patients, and to determine the effects of apremilast on AD-related inflammatory markers in vitro and in murine models of AD.
The expression of PDE4 isoforms (A, B, C, and D) in skin biopsies from healthy subjects and AD patients was evaluated using immunohistochemistry and digital image analysis. Using quantitative real-time reverse-transcriptase polymerase chain reaction, we evaluated the effects of apremilast on gene expression in adult human epidermal keratinocytes (HEKa) stimulated by Th2 and Th17 cytokines, and in two mouse models of antigen-induced AD.
Expression of PDE4 isoforms increased up to three-fold in the epidermis of AD patients versus healthy skin. In interleukin (IL)-4 and IL-17-stimulated HEKa cells, apremilast significantly changed the expression of ILs, including IL-12/IL-23p40 and IL-31, and alarmins S100A7, S100A8, and S100A12. In mouse models of AD, apremilast significantly reduced ear swelling and monocyte chemoattractant protein-1 expression.
PDE4 is overexpressed in AD skin compared with normal skin, and inflammatory gene expression by human keratinocytes and mouse dermatitis can be modulated by apremilast.
阿普米司特是一种口服磷酸二酯酶（PDE）4 抑制剂，已被证实对银屑病有效，但其在特应性皮炎（AD）中的疗效则较为有限。AD 是一种慢性炎症性皮肤病，与辅助性 T 细胞（Th）2 和 Th17 免疫激活以及表皮屏障受损有关。
本研究旨在检测 PDE4 同工型在健康受试者和 AD 患者皮肤中的表达情况，并确定阿普米司特在体外和 AD 小鼠模型中对 AD 相关炎症标志物的作用。
采用免疫组织化学和数字图像分析评估 PDE4 同工型（A、B、C 和 D）在健康受试者和 AD 患者皮肤活检组织中的表达情况。采用实时定量逆转录聚合酶链反应（qRT-PCR）评估阿普米司特对 Th2 和 Th17 细胞因子刺激的成人表皮角质形成细胞（HEKa）以及两种抗原诱导的 AD 小鼠模型中基因表达的影响。
与健康皮肤相比，AD 患者的表皮中 PDE4 同工型的表达增加了 2-3 倍。在白细胞介素（IL）-4 和 IL-17 刺激的 HEKa 细胞中，阿普米司特显著改变了包括 IL-12/IL-23p40 和 IL-31 在内的 IL 以及 S100A7、S100A8 和 S100A12 等警报素的表达。在 AD 小鼠模型中，阿普米司特显著降低了耳部肿胀和单核细胞趋化蛋白-1 的表达。
与正常皮肤相比，AD 皮肤中 PDE4 表达过度，阿普米司特可调节人角质形成细胞和小鼠皮炎的炎症基因表达。
