The phosphodiesterase 4 inhibitor apremilast inhibits Th1 but promotes Th17 responses induced by 6-sulfo LacNAc (slan) dendritic cells. Issue 2 (August 2017)

• Record Type: Journal Article
• Authors: Oehrl, Stephanie; Prakash, Hridayesh; Ebling, Annette; Trenkler, Nina; Wölbing, Priscila; Kunze, Anja; Döbel, Thomas; Schmitz, Marc; Enk, Alexander; Schäkel, Knut
• Is Part Of: Journal of dermatological science. Volume 87:Issue 2(2017:Aug.)
• Page Start: 110
• Page End: 115
• Publication Date: 2017-08
• Subjects: cAMP cyclic adenosine monophosphate -- slanDC 6-Sulfo LacNAc-expressing dendritic -- cells PDE phosphodiesterase -- Th17 T helper cells producing interleukin 17 -- Th1 T helper cells producing interferon gamma -- TNF-α Tumor necrosis factor alpha -- iNOS inducible nitric oxide synthase -- TIP-DC TNF-α and iNOS-producing dendritic cells -- RORγt retinoic acid receptor-related orphan receptor C -- T-bet T-box transcription factor; slanDCs -- Psoriasis -- cAMP -- T cell responses -- PDE4 inhibitor -- Apremilast; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2017.04.005
• Languages: English
• ISSNs: 0923-1811

Abstract

Highlights: Apremilast reduces TNF-α and IL-12 but enhances IL-23 and IL-1ß production by slanDCs. Apremilast-treated slanDCs induced enhanced Th17 T cell responses. Abstract: Background: 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. Objective: The aim of this study was to investigate possible immune regulatory effects of the PDE4 inhibitor apremilast on slanDCs. Methods: 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. Results: 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. Conclusions: 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.