Abstract
The molecular mechanisms by which mesenchymal stem cells (MSCs) suppress T-cell proliferation are poorly understood, and whether a soluble factor plays a major role remains controversial. Here we demonstrate that the T-cell-receptor complex is not a target for the suppression, suggesting that downstream signals mediate the suppression. We found that Stat5 phosphorylation in T cells is suppressed in the presence of MSCs and that nitric oxide (NO) is involved in the suppression of Stat5 phosphorylation and T-cell proliferation. The induction of inducible NO synthase (NOS) was readily detected in MSCs but not T cells, and a specific inhibitor of NOS reversed the suppression of Stat5 phosphorylation and T-cell proliferation. This production of NO in the presence of MSCs was mediated by CD4 or CD8 T cells but not by CD19 B cells. Furthermore, inhibitors of prostaglandin synthase or NOS restored the proliferation of T cells, whereas an inhibitor of indoleamine 2,3-dioxygenase and a transforming growth factor-beta-neutralizing antibody had no effect. Finally, MSCs from inducible NOS-/- mice had a reduced ability to suppress T-cell proliferation. Taken together, these results suggest that NO produced by MSCs is one of the major mediators of T-cell suppression by MSCs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD19 / analysis
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B-Lymphocyte Subsets / cytology
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B-Lymphocyte Subsets / drug effects
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B-Lymphocyte Subsets / metabolism
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / metabolism
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Cell Division / drug effects
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Cell Line
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Concanavalin A / pharmacology
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / physiology
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Enzyme Induction / drug effects
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HeLa Cells
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Humans
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Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
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Indoleamine-Pyrrole 2,3,-Dioxygenase / physiology
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Interferon-gamma / biosynthesis
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Interleukin-2 / biosynthesis
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Ionomycin / pharmacology
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Lymphocyte Activation / drug effects
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Macrophages / physiology
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Mesenchymal Stem Cells / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NG-Nitroarginine Methyl Ester / pharmacology
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Nitric Oxide / biosynthesis
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Nitric Oxide / pharmacology
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Nitric Oxide / physiology*
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / deficiency
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Nitric Oxide Synthase Type II / metabolism
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Phosphorylation / drug effects
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Prostaglandin-Endoperoxide Synthases / physiology
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Protein Processing, Post-Translational / drug effects
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Receptors, Antigen, T-Cell / physiology
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STAT5 Transcription Factor / metabolism
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Signal Transduction
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / drug effects*
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Tetradecanoylphorbol Acetate / pharmacology
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / immunology
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Tryptophan / analogs & derivatives
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Tryptophan / pharmacology
Substances
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Antigens, CD19
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Cyclooxygenase Inhibitors
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Interleukin-2
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Receptors, Antigen, T-Cell
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STAT5 Transcription Factor
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Transforming Growth Factor beta
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Concanavalin A
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Nitric Oxide
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Ionomycin
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Interferon-gamma
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Tryptophan
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Nitric Oxide Synthase Type II
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone
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Tetradecanoylphorbol Acetate
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NG-Nitroarginine Methyl Ester