Huang F P, Feng G J, Lindop G, Stott D I, Liew F Y
Department of Immunology, University of Glasgow, United Kingdom.
J Exp Med. 1996 Apr 1;183(4):1447-59. doi: 10.1084/jem.183.4.1447.
MRL/MP-lpr/lpr (MRL/lpr) mice develop a spontaneous autoimmune disease. Serum from these mice contained significantly higher concentrations of nitrite/nitrate than serum from age-matched control MRL/MP-+/+ (MRL/+), BALB/c or CBA/6J mice. Spleen and peritoneal cells from MRL/lpr mice also produced significantly more nitric oxide (NO) than those from the control mice when cultured with interferon (IFN) gamma and lipopolysaccharide (LPS) in vitro. It is interesting to note that peritoneal cells from MRL/lpr mice also produced markedly higher concentrations of interleukin (IL) 12 than those from MRL/+ or BALB/c mice when cultured with same stimuli. It is striking that cells from MRL/lpr mice produced high concentrations of NO when cultured cells from MRL/+ or BALB/c mice. The enhanced NO synthesis induced by IFN-gamma/LPS was substantially inhibited by anti-IL-12 antibody. In addition, IL-12-induced NO production can also be markedly inhibited by anti-IFN-gamma antibody, but only weakly inhibited by anti-tumor necrosis factor alpha antibody. The effect of IL-12 on NO production was dependent on the presence of natural killer and possibly T cells. Serum from MRL/lpr mice contained significantly higher concentrations of IL-12 compared with those of MRL/+ or BALB/c control mice. Daily injection of recombinant IL-12 led to increased serum levels of IFN-gamma and NO metabolites, and accelerated glomerulonephritis in the young MRL/lpr mice (but not in the MRL/+ mice) compared with controls injected with phosphate-buffered saline alone. These data, together with previous finding that NO synthase inhibitors can ameliorate autoimmune disease in MRL/lpr mice, suggest that high capacity of such mice to produce IL-12 and their greater responsiveness to IL-12, leading to the production of high concentrations of NO, are important factors in this spontaneous model of autoimmune disease.
MRL/MP-lpr/lpr（MRL/lpr）小鼠会发生自发性自身免疫疾病。这些小鼠血清中的亚硝酸盐/硝酸盐浓度显著高于年龄匹配的对照MRL/MP-+/+（MRL/+）、BALB/c或CBA/6J小鼠的血清。当在体外与干扰素（IFN）γ和脂多糖（LPS）一起培养时，MRL/lpr小鼠的脾脏和腹腔细胞产生的一氧化氮（NO）也明显多于对照小鼠。值得注意的是，当用相同刺激物培养时，MRL/lpr小鼠的腹腔细胞产生的白细胞介素（IL）12浓度也明显高于MRL/+或BALB/c小鼠。令人惊讶的是，当用MRL/+或BALB/c小鼠的细胞培养时，MRL/lpr小鼠的细胞会产生高浓度的NO。IFN-γ/LPS诱导的NO合成增强被抗IL-12抗体显著抑制。此外，抗IFN-γ抗体也能显著抑制IL-12诱导的NO产生，但抗肿瘤坏死因子α抗体只能微弱抑制。IL-12对NO产生的作用取决于自然杀伤细胞以及可能的T细胞的存在。与MRL/+或BALB/c对照小鼠相比，MRL/lpr小鼠血清中的IL-12浓度显著更高。与仅注射磷酸盐缓冲盐水的对照相比，每天注射重组IL-12会导致年轻MRL/lpr小鼠（但MRL/+小鼠不会）的血清IFN-γ和NO代谢产物水平升高，并加速肾小球肾炎。这些数据，连同先前发现一氧化氮合酶抑制剂可改善MRL/lpr小鼠的自身免疫疾病，表明此类小鼠产生IL-12的能力高以及它们对IL-12的反应性更强，导致产生高浓度的NO，是这种自身免疫疾病自发模型中的重要因素。
