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

Research output: Contribution to journal › Research article › Contributed › peer-review

Contributors

  • Stephanie Oehrl - , University Hospital Heidelberg (Author)
  • Hridayesh Prakash - , University Hospital Heidelberg (Author)
  • Annette Ebling - , Institute for Immunology (Author)
  • Nina Trenkler - , University Hospital Heidelberg (Author)
  • Priscila Wölbing - , University Hospital Heidelberg (Author)
  • Anja Kunze - , University Hospital Heidelberg (Author)
  • Thomas Döbel - , University Hospital Heidelberg (Author)
  • Marc Schmitz - , Institute for Immunology (Author)
  • Alexander Enk - , University Hospital Heidelberg (Author)
  • Knut Schäkel - , University Hospital Heidelberg (Author)

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.

Details

Original languageEnglish
Pages (from-to)110-115
Number of pages6
JournalJournal of dermatological science
Volume87
Issue number2
Publication statusPublished - Aug 2017
Peer-reviewedYes

External IDs

PubMed 28499587

Keywords

Sustainable Development Goals

Keywords

  • Apremilast, cAMP, PDE4 inhibitor, Psoriasis, slanDCs, T cell responses