0583: Toll-Like Receptor Ligands Stimulated Monocyte-Derived Langerhans Cell-Like Dendritic Cells Induce Psoriasis-Related Molecules, IL-23 and Delta-Like-4

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.