Rei Takahashi1, Kohei Maeda1, Toshihiro Tanioka1 and Takeo Isozaki2, 1Division of Pathogenesis and Translational Medicine, Department of Clinical Pharmacy, Showa University School of Pharmacy, Tokyo, Japan, 2Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
Background/Purpose: Monocyte-derived Langerhans cell-like dendritic cells (Mo-LCs) are involved in epidermal disorders such as psoriasis in murine models. However, the roles of Mo-LCs in the pathogenesis of psoriasis in humans remain unclear because the optimal method of Mo-LC generation remains unidentified. Here, we investigated the necessary factors inducing Mo-LCs and the relationship between the Mo-LCs and the pathogenesis of psoriasis.
Methods: Peripheral blood monocytes via the initial stimulation with immobilized notch ligands, transforming growth factor (TGF)-β1, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed the percentage of the Langerin+ cells designated Mo-LCs by FACS. The Mo-LCs were compared with the dendritic cells derived from monocytes (Mo-DCs) cultured with interleukin (IL)-4 and GM-CSF, and M1 macrophages (Mφ) derived from monocytes cultured with GM-CSF after stimulation with toll-like receptor (TLR) ligands in the analysis of FACS and real-time PCR.
Results: We established a new method of stimulating CD14+ monocytes with immobilized human notch ligand delta-like (DLL)-1 to generate Mo-LCs. We also found that DLL-1 and DLL-4 had a significantly higher rate of differentiation induction than the other NOTCH families and conventional Mo-LC inducers (60 %, 50 %, and 0-1.2 %, respectively). Furthermore, DLL-1 and DLL-4 synergistically induced Mo-LCs. The Mo-LCs were found to produce significant amounts of IL-15, IL-23 and express DLL-4, which are related to the pathology of psoriasis, in response to the TLR ligands compared with Mo-DCs and Mφ.
Conclusion: We established a new method to generate Mo-LCs. We also found that the Mo-LCs produce IL-15 and IL-23 and express DLL-4. Our results indicate that Mo-LCs are involved in the pathogenesis of psoriasis via notch signaling of DLL-1 and DLL-4 or TLR signaling pathway.
Disclosures: R. Takahashi, None; K. Maeda, None; T. Tanioka, None; T. Isozaki, None.