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Blood, 1 January 2007, Vol. 109, No. 1, pp. 228-234. Prepublished online as a Blood First Edition Paper on September 19, 2006; DOI 10.1182/blood-2006-02-002246. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-02-002246v1 109/1/228    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sato, K. Articles by Ozawa, K. Search for Related Content PubMed PubMed Citation Articles by Sato, K. Articles by Ozawa, K. Related Collections Immunobiology Signal Transduction Stem Cells in Hematology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells Kazuya Sato1, Katsutoshi Ozaki1,, Iekuni Oh1, Akiko Meguro1, Keiko Hatanaka1, Tadashi Nagai1, Kazuo Muroi1, and Keiya Ozawa1, 1 Division of Hematology, Jichi Medical University, Tochigi, Japan 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–ß–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. 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