Oehrl Stephanie, Prakash Hridayesh, Ebling Annette, Trenkler Nina, Wölbing Priscila, Kunze Anja, Döbel Thomas, Schmitz Marc, Enk Alexander, Schäkel Knut
Department of Dermatology, University Hospital Heidelberg, Germany.
Institute of Immunology, Technical University of Dresden, Germany.
J Dermatol Sci. 2017 Aug;87(2):110-115. doi: 10.1016/j.jdermsci.2017.04.005. Epub 2017 Apr 20.
The phosphodiesterase 4 (PDE4) inhibitor apremilast increases cellular cAMP levels and has proven effective in the treatment of psoriasis and psoriasis arthritis. We recently described 6-sulfo LacNAc dendritic cells (slanDCs) as immature DCs in blood and as a subset of inflammatory dermal DCs in psoriasis with a pronounced capacity to produce proinflammatory cytokines and to program Th17/Th1 T cell responses.
The aim of this study was to investigate possible immune regulatory effects of the PDE4 inhibitor apremilast on slanDCs.
In vitro studies were performed analyzing the effects of apremilast on the proinflammatory function of slanDCs and their capacity to induce Th1/Th17-biased T cell responses.
Increasing cAMP levels in slanDCs by PDE4 inhibition strongly reduced production of IL-12 and TNF-α. In line with these findings, co-culture experiments with apremilast-pulsed slanDCs and allogeneic T cells either from psoriasis patients or healthy controls, revealed a significant reduction of IFN-γ production and expression of the transcription factor T-bet. In parallel, production of IL-23 and IL-1ß by slanDCs was increased and co-cultured T cells revealed a largely augmented IL-17 production and an upregulated RORyt expression.
We here demonstrate anti-inflammatory as well as Th17-promoting effects of apremilast when studying blood precursors of human inflammatory dermal dendritic cells. In the concert of the broad anti-inflammatory effects of apremilast on keratinocytes, fibroblasts and endothelial cells, the dual effect on slan inflammatory dermal DCs should be taken into account and may constrain therapeutic responses.
磷酸二酯酶4（PDE4）抑制剂阿普斯特可提高细胞内环磷酸腺苷（cAMP）水平，已被证明对治疗银屑病和银屑病关节炎有效。我们最近将6-磺基乳糖胺聚糖树突状细胞（slanDCs）描述为血液中的未成熟树突状细胞，以及银屑病中炎症性真皮树突状细胞的一个亚群，其具有显著的产生促炎细胞因子和调控Th17/Th1 T细胞反应的能力。
本研究旨在探讨PDE4抑制剂阿普斯特对slanDCs可能的免疫调节作用。
进行体外研究，分析阿普斯特对slanDCs促炎功能及其诱导Th1/Th17偏向性T细胞反应能力的影响。
通过抑制PDE4提高slanDCs中的cAMP水平，可强烈降低白细胞介素-12（IL-12）和肿瘤坏死因子-α（TNF-α）的产生。与这些发现一致，用阿普斯特预处理的slanDCs与来自银屑病患者或健康对照的同种异体T细胞进行共培养实验，结果显示干扰素-γ（IFN-γ）产生和转录因子T-bet表达显著降低。同时，slanDCs产生的白细胞介素-23（IL-23）和白细胞介素-1β（IL-1β）增加，共培养的T细胞显示白细胞介素-17产生大量增加且维甲酸相关孤儿受体γt（RORyt）表达上调。
我们在此证明，在研究人类炎症性真皮树突状细胞的血液前体细胞时，阿普斯特具有抗炎以及促进Th17细胞的作用。鉴于阿普斯特对角质形成细胞、成纤维细胞和内皮细胞具有广泛的抗炎作用，其对slan炎症性真皮树突状细胞的双重作用应予以考虑，这可能会限制治疗反应。
