title: Iminosugar derivative WGN-26 suppresses acute allograft rejection via inhibiting the IFN-γ/p-STAT1/T-bet signaling pathway.
abstract: This study aimed to investigate the effect of the iminosugar derivative WGN-26 on suppressing acute allograft rejection and to explore the underlying mechanisms. The results demonstrated that WGN-26 (12, 6 and 3mg/kg) significantly prolonged the skin allograft survival time in a dose-dependent manner and minimized the pathological changes. The minimum lethal dose was 320 mg/kg. By exploring the potential cellular and molecular mechanisms, we found that WGN-26 dose-dependently inhibited T lymphocyte proliferation, as determined through the single mixed lymphocyte reaction (sMLR) or the ConA-induced T cell proliferation assay in allograft recipients. The FCM results indicated that WGN-26 particularly reduced the percentage of CD3(+)CD4(+) T cells in allograft recipients. After treatment with WGN-26, the secretion of IFN-γ in allograft recipients was lowered, whereas the IL-4 and IL-17 levels remained stable. Furthermore, we found that WGN-26 inhibited the phosphorylation of STAT1 and accelerated the degradation of T-bet protein in allograft recipients. This study provides the first report that the iminosugar derivative WGN-26 dose-dependently prolongs skin allograft survival and that the possible mechanism is mediated by inhibiting CD4(+) T cell proliferation and suppressing the IFN-γ/p-STAT1/T-bet signaling pathway.
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China; Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Yangguang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China; Institute of Mental Health, Peking University, Beijing 100191, PR China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Guannan
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: xinshan@bjmu.edu.cn.
authors.forename: Xinshan
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: yejia@bjmu.edu.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Ye
mesh_terms: D000208:Acute Disease; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D050111:Imino Sugars / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016038:Skin Transplantation; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D020825:T-Box Domain Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: C000599730:1-decylpyrrolidine-3,4-diol; D050111:Imino Sugars; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma
keywords: IFN-γ; Iminosugar derivative WGN-26; Skin allograft; p-STAT1/T-bet signaling pathway