title: Mesenchymal stem cells tune the development of monocyte-derived dendritic cells toward a myeloid-derived suppressive phenotype through growth-regulated oncogene chemokines.
abstract: Mesenchymal stem/stromal cells (MSCs) are promising potential candidates for the treatment of immunological diseases because of their immunosuppressive functions. However, the molecular mechanisms that mediate MSCs' immunosuppressive activity remain elusive. In this article, we report for the first time, to our knowledge, that secreted growth-regulated oncogene (GRO) chemokines, specifically GRO-γ, in human MSC-conditioned media have an effect on the differentiation and the function of human monocyte-derived dendritic cells. The monocyte-derived dendritic cells were driven toward a myeloid-derived suppressor cell (MDSC)-like phenotype by the GRO chemokines. GRO-γ-treated MDSCs had a tolerogenic phenotype that was characterized by an increase in the secretion of IL-10 and IL-4, and a reduction in the production of IL-12 and IFN-γ. We have also shown that the mRNA expression levels of the arginase-1 and inducible NO synthase genes, which characterize MDSCs, were upregulated by GRO-γ-primed mouse bone marrow cells. In addition, the ability of GRO-γ-treated bone marrow-derived dendritic cells to stimulate the OVA-specific CD8(+) T (OT-1) cell proliferation and the cytokine production of IFN-γ and TNF-α were significantly decreased in vivo. Our findings allow a greater understanding of how MDSCs can be generated and offer new perspectives to exploit the potential of MDSCs for alternative approaches to treat chronic inflammation and autoimmunity, as well as for the prevention of transplant rejection.
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
authors.forename: Hsin-Wei
authors.initials: HW
authors.lastname: Chen
authors.forename: Hsin-Yu
authors.initials: HY
authors.lastname: Chen
authors.forename: Li-Tzu
authors.initials: LT
authors.lastname: Wang
authors.forename: Fu-Hui
authors.initials: FH
authors.lastname: Wang
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Fang
authors.forename: Hsiu-Yu
authors.initials: HY
authors.lastname: Lai
authors.forename: Hsuan-Hsu
authors.initials: HH
authors.lastname: Chen
authors.forename: Jean
authors.initials: J
authors.lastname: Lu
authors.forename: Ming-Shiu
authors.initials: MS
authors.lastname: Hung
authors.forename: Yao
authors.initials: Y
authors.lastname: Cheng
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Chen
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Liu
authors.forename: Pele
authors.initials: P
authors.lastname: Chong
authors.forename: Oscar Kuang-Sheng
authors.initials: OK
authors.lastname: Lee
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Hsu
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000235:genetics; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000494:pharmacology; D054426:Chemokine CXCL2 / Q000494:pharmacology; D019743:Chemokines, CXC / Q000378:metabolism* / Q000502:physiology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C475829:CXCL1 protein, human; C499706:CXCL2 protein, human; C499707:CXCL3 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C544448:Arg1 protein, mouse; D001119:Arginase