Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells.
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.
Sato
Kazuya
K
Division of Hematology, Jichi Medical University, 3311-1 Yakushiji, Tochigi 329-0498, Japan.
Ozaki
Katsutoshi
K
Oh
Iekuni
I
Meguro
Akiko
A
Hatanaka
Keiko
K
Nagai
Tadashi
T
Muroi
Kazuo
K
Ozawa
Keiya
K
D000818:Animals; D018941:Antigens, CD19 / Q000032:analysis; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003208:Concanavalin A / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
D018941:Antigens, CD19; D016861:Cyclooxygenase Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; D016212:Transforming Growth Factor beta; D003208:Concanavalin A; D009569:Nitric Oxide; D015759:Ionomycin; D007371:Interferon-gamma; D014364:Tryptophan; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D019331:NG-Nitroarginine Methyl Ester