Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis.

Autor: Inuki S; Graduate School of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan.; Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan., Hirata N; Graduate School of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan., Kashiwabara E; Graduate School of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan., Kishi J; Graduate School of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan., Aiba T; Graduate School of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan.; Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama-cho, Toyonaka, Osaka, 560-0043, Japan., Teratani T; School of Medicine, Keio University, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan., Nakamura W; Discovery and Research, ONO Pharmaceutical Co., Ltd., Sakurai, Shimamoto, Mishima, Osaka, 618-8585, Japan., Kojima Y; Discovery and Research, ONO Pharmaceutical Co., Ltd., Sakurai, Shimamoto, Mishima, Osaka, 618-8585, Japan., Maruyama T; Discovery and Research, ONO Pharmaceutical Co., Ltd., Sakurai, Shimamoto, Mishima, Osaka, 618-8585, Japan., Kanai T; School of Medicine, Keio University, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan., Fujimoto Y; Graduate School of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan. fujimotoy@chem.keio.ac.jp.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2020 Sep 25; Vol. 10 (1), pp. 15766. Date of Electronic Publication: 2020 Sep 25.
DOI: 10.1038/s41598-020-72280-4
Abstrakt: The MHC class I-like molecule CD1d is a nonpolymorphic antigen-presenting glycoprotein, and its ligands include glycolipids, such as α-GalCer. The complexes between CD1d and ligands activate natural killer T cells by T cell receptor recognition, leading to the secretion of various cytokines (IFN-γ, IL-4, IL-17A, etc.). Herein, we report structure-activity relationship studies of α-GalCer derivatives containing various functional groups in their lipid acyl chains. Several derivatives have been identified as potent CD1d ligands displaying higher cytokine induction levels and/or unique cytokine polarization. The studies also indicated that flexibility of the lipid moiety can affect the binding affinity, the total cytokine production level and/or cytokine biasing. Based on our immunological evaluation and investigation of physicochemical properties, we chose bisamide- and Bz amide-containing derivatives 2 and 3, and evaluated their in vivo efficacy in a DSS-induced model of ulcerative colitis. The derivative 3 that exhibits Th2- and Th17-biasing responses, demonstrated significant protective effects against intestinal inflammation in the DSS-induced model, after a single intraperitoneal injection.
Databáze: MEDLINE
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