Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway.
Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway.
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DOI：
10.4049/jimmunol.147.1.144
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发表时间：
1991-07
影响因子：
4.4
通讯作者：
J. Albina;J. Abate;W. Henry
中科院分区：
文献类型：
--
作者：
J. Albina;J. Abate;W. Henry
通过添加过量的巨噬细胞抑制Con A或LPS刺激的小鼠脾细胞（SC）培养物中的淋巴细胞增殖。在Con A刺激的培养物中，抑制与一氧化氮合成途径（NOSP）活性的表达相关，如培养上清液中一氧化氮（NO）降解产物亚硝酸盐的积累所证明的。通过向培养基中添加NOSP的特异性抑制剂（NG-单甲基-L-精氨酸乙酸酯）所引起的抑制逆转，表明NO（L-精氨酸的细胞毒性和抗增殖代谢物）或通过NOSP介导的抑制作用产生的其它活性氮中间体。在LPS刺激的SC/巨噬细胞共培养物中未检测到NOSP活性。通过使用抗IFN-γ-mAb研究T细胞衍生的IFN-γ在NOSP诱导中的作用。抗体处理的Con A上清液不能诱导巨噬细胞中的NOSP，并且将mAb添加到Con A刺激的SC/巨噬细胞共培养物中消除了抑制作用。吲哚美辛和过氧化氢酶仅部分恢复ConA刺激的SC/巨噬细胞共培养物中的增殖，但当LPS用作促有丝分裂刺激时，它们在防止巨噬细胞依赖性抑制方面非常有效。这些结果证明了在主要巨噬细胞浸润的位点中具有潜在相关性的调节系统，通过该调节系统，T细胞衍生的IFN-γ激活抑制T细胞增殖的介体NO的产生。此外，这些数据表明，尽管过量巨噬细胞的抑制作用似乎对T和B细胞都是非特异性表达的，但在每种情况下，抑制是通过不同的机制介导的。
Lymphocyte proliferation in Con A- or LPS-stimulated murine splenic cell (SC) cultures was suppressed by the addition of excess macrophages. In Con A-stimulated cultures, suppression was associated with the expression of nitric oxide-synthesizing pathway (NOSP) activity as demonstrated by the accumulation of nitrite, a degradation product of nitric oxide (NO), in the culture supernatants. That NO, a cytotoxic and anti-proliferative metabolite of l-arginine, or other reactive nitrogen intermediates generated through the NOSP mediated the suppressive effect was suggested by the reversal of suppression brought about by the addition of a specific inhibitor of the NOSP (NG-monomethyl-l-arginine acetate) to the culture media. No NOSP activity was detectable in LPS-stimulated SC/macrophage cocultures. The role of T cell-derived IFN-gamma in the induction of the NOSP was investigated by the use of anti-IFN-gamma-mAb. Antibody-treated Con A supernatants failed to induce the NOSP in macrophages, and the addition of the mAb to Con A-stimulated SC/macrophage cocultures obviated the suppressive effects. Indomethacin and catalase only partially restored proliferation in Con A-stimulated SC/macrophage cocultures but were remarkably efficient in preventing macrophage-dependent suppression when LPS was used as the mitogenic stimulus. These results demonstrate a regulatory system of potential relevance in sites of predominant macrophage infiltration by which T cell-derived IFN-gamma activates the production of the mediator, NO, that suppresses T cell proliferation. In addition, these data demonstrate that, although the suppressive effects of excess macrophages appear to be expressed nonspecifically toward both T and B cells, suppression is mediated through a different mechanism in each case.