title: Functional changes in myeloid-derived suppressor cells (MDSCs) during tumor growth: FKBP51 contributes to the regulation of the immunosuppressive function of MDSCs.
abstract: Myeloid-derived suppressor cells (MDSCs) are increased by tumor-derived factors and suppress anti-tumor immunity. MDSCs obtained at a late time point after tumor injection had stronger suppressive activity than MDSCs obtained at an early time point, as measured by T cell proliferation assays. To find factors in MDSCs that change during tumor growth, we analyzed gene expression profiles from MDSCs at different time points after tumor injection. We found that immune response-related genes were downregulated but protumor function-related genes were upregulated in both monocytic MDSCs (Mo-MDSCs) and polymorphonuclear granulocytic MDSCs (PMN-MDSCs) at the late time point. Among differentially expressed genes, FK506 binding protein 51 (FKBP51), which is a member of the immunophilin protein family and plays a role in immunoregulation, was increased in the Mo-MDSCs and PMN-MDSCs isolated from the late time points. Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity. Collectively, our data suggest that FKBP51 is a novel molecule that can be targeted to regulate the immunosuppressive function of MDSCs.
authors.affiliation: Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Yun-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Yeon-Jeong
authors.initials: YJ
authors.lastname: Kim
authors.forename: Jung-Mi
authors.initials: JM
authors.lastname: Lee
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Park
authors.forename: Su-Kyong
authors.initials: SK
authors.lastname: Choe
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Ko
authors.forename: Chang-Yuil
authors.initials: CY
authors.lastname: Kang
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000276:immunology; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D022021:Tacrolimus Binding Proteins / Q000096:biosynthesis / Q000276:immunology*; D013997:Time Factors; D000099159:Tacrolimus Binding Protein 5
chemical_list: D001119:Arginase; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019001:Nitric Oxide Synthase; D017382:Reactive Oxygen Species; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C544448:Arg1 protein, mouse