title: High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia.
abstract: Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. In this study, the MDSC population was evaluated in adult patients with primary immune thrombocytopenia (ITP), where cell-mediated immune mechanisms are involved in platelet destruction. Our data demonstrated that both the numbers and suppressive functions of MDSCs were impaired in the peripheral blood and spleens of patients with ITP compared with healthy control patients. High-dose dexamethasone (HD-DXM) treatment rescued MDSC numbers in patients with ITP. And DXM modulation promoted the suppressive function of MDSCs induced in vitro. Moreover, the expression of interleukin 10 and transforming growth factor β was significantly upregulated in DXM-modulated MDSCs compared with the unmodulated cultures. DXM-modulated MDSCs inhibited autologous CD4(+)T-cell proliferation and significantly attenuated cytotoxic T lymphocyte-mediated platelet lysis, further indicating enhanced control over T-cell responses. Elevated expression of the transcription factor Ets1 was identified in DXM-modulated MDSCs. Transfection of Ets-1 small interfering RNA efficiently blocked regulatory effects of MDSCs, which almost offset the augmentation of MDSC function by DXM. Meanwhile, splenocytes from CD61 knockout mice immunized with CD61(+)platelets were transferred into severe combined immunodeficient (SCID) mouse recipients (C57/B6 background) to induce a murine model of severe ITP. We passively transferred the DXM-modulated MDSCs induced from bone marrow of wild-type C57/B6 mice into the SCID mouse recipients, which significantly increased platelet counts in vivo compared with those receiving splenocyte engraftment alone. These findings suggested that impaired MDSCs are involved in the pathogenesis of ITP, and that HD-DXM corrected MDSC functions via a mechanism underlying glucocorticoid action and Ets1.
authors.affiliation: Department of Hematology and Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China;
authors.forename: Yu
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Hematology and Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China;
authors.forename: Qi
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Department of Hematology and.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China;
authors.forename: Guo-Sheng
authors.initials: GS
authors.lastname: Li
authors.affiliation: Department of Hematology and.
authors.forename: Xue-Na
authors.initials: XN
authors.lastname: Liu
authors.affiliation: Department of Hematology and.
authors.forename: Zi
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: Department of Hematology and.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, Shandong Cancer Hospital and Institute, Jinan, China; and.
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Hematology and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Hematology and.
authors.forename: Yuan-Xin
authors.initials: YX
authors.lastname: Sun
authors.affiliation: Department of Hematology and.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Yu
authors.affiliation: Department of Hematology and.
authors.forename: Ji-Hua
authors.initials: JH
authors.lastname: Qiu
authors.affiliation: Department of Hematology and.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Shao
authors.affiliation: Department of Hematology and.
authors.forename: Xin-Guang
authors.initials: XG
authors.lastname: Liu
authors.affiliation: Department of Hematology and Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Hou
authors.affiliation: Department of Hematology and Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000276:immunology; D003907:Dexamethasone / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008875:Middle Aged; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D050784:Proto-Oncogene Protein c-ets-1 / Q000276:immunology*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D003907:Dexamethasone