Abstract
Myeloid-derived suppressor cells (MDSC) are one of the main cell populations that negatively regulate immune responses. However, the mechanism underlying the expansion of MDSC remains unclear. Using miRNA microarray and TaqMan probe-based quantitative RT-PCR assay, we identified microRNA (miR)-155 and miR-21 as the two most upregulated miRNAs during the induction of MDSC from the bone marrow cells by GM-CSF and IL-6. High levels of miR-155 and miR-21 also were detected in bone marrow and spleen MDSC isolated from tumor-bearing mice. Our results also showed that TGF-β promoted the induction of MDSC through upregulating miR-155 and miR-21 expression. Overexpression of miR-155 and miR-21 enhanced whereas depletion of miR-155 and miR-21 reduced the frequencies of cytokine-induced MDSC. Subpopulation analysis indicated that miR-21 and miR-155 induced the expansion of both monocytic and granulocytic MDSC. Furthermore, miR-155 and miR-21 showed a synergistic effect on MDSC induction via targeting SHIP-1 and phosphatase and tensin homolog, respectively, leading to STAT3 activation. Finally, dexamethasone treatment strongly enhanced MDSC expansion through upregulating miR-155 and miR-21 expression, and the effect of dexamethasone on MDSC induction was abolished by depleting cellular miR-155 and miR-21. These results demonstrate a novel miR-155/miR-21-based regulatory mechanism that modulates functional MDSC induction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / drug effects
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Carcinoma, Lewis Lung / pathology
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Cells, Cultured
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Dexamethasone / pharmacology
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Inositol Polyphosphate 5-Phosphatases
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Interleukin-6 / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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MicroRNAs / antagonists & inhibitors
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MicroRNAs / biosynthesis
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MicroRNAs / genetics
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MicroRNAs / physiology*
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Myeloid Cells / classification
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Myeloid Cells / cytology*
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Myeloid Cells / pathology
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Oligonucleotide Array Sequence Analysis
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PTEN Phosphohydrolase / antagonists & inhibitors
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
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Phosphoric Monoester Hydrolases / antagonists & inhibitors
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Phosphoric Monoester Hydrolases / metabolism
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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RNA, Small Interfering / pharmacology
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / metabolism
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Transforming Growth Factor beta1 / pharmacology
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Up-Regulation / drug effects
Substances
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Interleukin-6
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MIRN21 microRNA, mouse
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MicroRNAs
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Mirn155 microRNA, mouse
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RNA, Neoplasm
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RNA, Small Interfering
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Transforming Growth Factor beta1
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interleukin-6, mouse
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Dexamethasone
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Granulocyte-Macrophage Colony-Stimulating Factor
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Phosphoric Monoester Hydrolases
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Inositol Polyphosphate 5-Phosphatases
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PTEN Phosphohydrolase
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Pten protein, mouse
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Inpp5d protein, mouse
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Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases