Huang F P, Niedbala W, Wei X Q, Xu D, Feng G J, Robinson J H, Lam C, Liew F Y
Department of Immunology, University of Glasgow, GB.
Eur J Immunol. 1998 Dec;28(12):4062-70. doi: 10.1002/(SICI)1521-4141(199812)28:12<4062::AID-IMMU4062>3.0.CO;2-K.
We have previously reported that mice lacking inducible nitric oxide synthase (NOS2) developed enhanced Th1 cell responses. We now investigated the mechanism by which NO modulates Th1 cells differentiation. Peritoneal macrophages from NOS2-deficient mice infected with Leishmania major in vivo or stimulated with IFN-gamma or lipopolysaccharide (LPS) in vitro produced significantly higher levels of IL-12 than those from heterozygous or wild-type mice. A macrophage cell line, J774, produced significant amounts of IL-12 following activation with LPS, or LPS plus IFN-gamma. This could be markedly enhanced by the NOS inhibitor L-NG monomethyl arginine (L-NMMA), but profoundly inhibited by the NO-generating compound S-nitroso-N-acetyl-penicillamine (SNAP). The effect of NO in this system is selective, since SNAP enhanced and L-NMMA decreased TNF-alpha synthesis by LPS-activated J774 cells. The differential effect of NO on IL-12 and TNF-alpha is at the transcriptional level and is activation dependent. Since IL-12 is a major inducer of Th1 cells which produce IFN-gamma that can activate macrophages to produce IL-12, our data demonstrate that NO can be an inhibitor of this feedback loop, preventing the excessive amplification of Th1 cells which are implicated in a range of immunopathologies.
我们之前报道过，缺乏诱导型一氧化氮合酶（NOS2）的小鼠会产生增强的Th1细胞反应。我们现在研究了NO调节Th1细胞分化的机制。在体内感染杜氏利什曼原虫或在体外经γ干扰素或脂多糖（LPS）刺激的NOS2缺陷小鼠的腹腔巨噬细胞，产生的白细胞介素-12（IL-12）水平显著高于杂合子或野生型小鼠的腹腔巨噬细胞。巨噬细胞系J774在经LPS或LPS加γ干扰素激活后产生大量IL-12。一氧化氮合酶抑制剂L-NG单甲基精氨酸（L-NMMA）可显著增强这种作用，但一氧化氮供体化合物S-亚硝基-N-乙酰青霉胺（SNAP）则可强烈抑制这种作用。在该系统中，NO的作用具有选择性，因为SNAP可增强LPS激活的J774细胞的肿瘤坏死因子-α（TNF-α）合成，而L-NMMA则降低其合成。NO对IL-12和TNF-α的不同作用发生在转录水平，且依赖于激活。由于IL-12是Th1细胞的主要诱导因子，Th1细胞产生的γ干扰素可激活巨噬细胞产生IL-12，因此我们的数据表明，NO可能是这种反馈回路的抑制剂，可防止Th1细胞过度扩增，Th1细胞过度扩增与一系列免疫病理相关。
