The phosphodiesterase 4 inhibitor apremilast inhibits Th1 but promotes Th17 responses induced by 6-sulfo LacNAc (slan) dendritic cells
| Autor: | Stephanie Oehrl, Hridayesh Prakash, Knut Schäkel, Nina Trenkler, Annette Ebling, Marc Schmitz, Priscila Wölbing, Anja Kunze, Alexander Enk, Thomas Döbel |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
T cell Dermatology Biology Biochemistry Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine Immune system Downregulation and upregulation RAR-related orphan receptor gamma Psoriasis Cyclic AMP medicine Humans Immunologic Factors Molecular Biology Tumor Necrosis Factor-alpha Amino Sugars Dendritic Cells Nuclear Receptor Subfamily 1 Group F Member 3 Th1 Cells medicine.disease Coculture Techniques In vitro Thalidomide 030104 developmental biology medicine.anatomical_structure Immunology Leukocytes Mononuclear Cytokines Th17 Cells Phosphodiesterase 4 Inhibitors Apremilast T-Box Domain Proteins 030215 immunology medicine.drug |
| Zdroj: | Journal of Dermatological Science. 87:110-115 |
| ISSN: | 0923-1811 |
| DOI: | 10.1016/j.jdermsci.2017.04.005 |
| Popis: | 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-1s 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect