Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells
Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells
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DOI：
10.1182/blood-2006-02-002246
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发表时间：
2007-01-01
期刊：
影响因子：
20.3
通讯作者：
Ozawa, Keiya
中科院分区：
文献类型：
--
作者：
Sato, Kazuya;Ozaki, Katsutoshi;Ozawa, Keiya
间充质干细胞(MSCs)抑制T细胞增殖的分子机制尚不清楚，其中是否有可溶性因子起主要作用仍存在争议。在这里，我们证明T细胞受体复合体不是抑制的目标，这表明下游信号介导了抑制。我们发现，在MSCs存在的情况下，T细胞中Stat5的磷酸化受到抑制，一氧化氮(NO)参与了对Stat5磷酸化的抑制和T细胞的增殖。诱导型一氧化氮合酶(NOS)的诱导在MSCs中很容易被检测到，但不能在T细胞中检测到，并且NOS的特异性抑制剂逆转了对Stat5磷酸化和T细胞增殖的抑制。在MSCs存在的情况下，这种NO的产生是由CD4或CD8T细胞介导的，而不是由CD19B细胞介导的。此外，前列腺素合成酶或一氧化氮合酶的抑制剂恢复了T细胞的增殖，而吲哚胺2，3-双加氧酶的抑制剂和转化生长因子-β中和抗体则没有作用。最后，来自可诱导的NOS-/-小鼠的MSCs抑制T细胞增殖的能力降低。综上所述，这些结果提示，MSCs产生的NO是MSCs抑制T细胞的主要介质之一。(C)美国血液病学会2007年
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. (c) 2007 by The American Society of Hematology