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

• Verfasst von: Oehrl, Stephanie [VerfasserIn]
• Verfasst von: Prakash, Hridayesh [VerfasserIn]
• Verfasst von: Trenkler, Nina [VerfasserIn]
• Verfasst von: Wölbing, Priscila [VerfasserIn]
• Verfasst von: Kunze, Anja [VerfasserIn]
• Verfasst von: Döbel, Thomas [VerfasserIn]
• Verfasst von: Enk, Alexander [VerfasserIn]
• Verfasst von: Schäkel, Knut [VerfasserIn]
• Titel: The phosphodiesterase 4 inhibitor apremilast inhibits Th1 but promotes Th17 responses induced by 6-sulfo LacNAc (slan) dendritic cells
• Verf.angabe: Stephanie Oehrl, Hridayesh Prakash, Annette Ebling, Nina Trenkler, Priscila Wölbing, Anja Kunze, Thomas Döbel, Marc Schmitz, Alexander Enk, Knut Schäkel
• E-Jahr: 2017
• Jahr: 20 April 2017
• Umfang: 6 S.
• Fussnoten: Available online 20 April 2017 ; Gesehen am 19.07.2018
• Titel Quelle: Enthalten in: Journal of dermatological science
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1990
• Jahr Quelle: 2017
• Band/Heft Quelle: 87(2017), 2, Seite 110-115
• ISSN Quelle: 1873-569X
• DOI: doi:10.1016/j.jdermsci.2017.04.005
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Apremilast
• Sach-SW: cAMP
• Sach-SW: PDE4 inhibitor
• Sach-SW: Psoriasis
• Sach-SW: slanDCs
• Sach-SW: T cell responses
• K10plus-PPN: 1577768345

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.