EFFECTS OF INTERFERON-GAMMA ON NITRIC-OXIDE SYNTHASE ACTIVITY AND ENDOTHELIN-1 PRODUCTION BY VASCULAR ENDOTHELIAL-CELLS
EFFECTS OF INTERFERON-GAMMA ON NITRIC-OXIDE SYNTHASE ACTIVITY AND ENDOTHELIN-1 PRODUCTION BY VASCULAR ENDOTHELIAL-CELLS
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DOI：
10.1172/jci115963
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发表时间：
1992-09-01
影响因子：
15.9
通讯作者：
MARSDEN, PA
中科院分区：
文献类型：
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作者：
LAMAS, S;MICHEL, T;MARSDEN, PA
鉴于 IFN-γ 在血管壁免疫疾病中的关键作用，我们研究了 IFN-γ 对牛主动脉内皮细胞 (BAEC) 中一氧化氮 (NO) 和内皮素-I (ET-1) 表达的影响。我们之前报道过，通过用报告单层定量生物活性NO的释放并测量L-[C-14]精氨酸到L-[C-14]瓜氨酸的转化来评估，TNF-α增强了BAEC中的NO合酶活性。在小鼠巨噬细胞中，IFN-γ 与 TNF-α 或脂多糖协同作用，诱导钙依赖性 NO 合酶活性的强劲增加。在这项研究中，我们发现单独使用 IFN-γ 未能对 BAEC 中的 NO 合酶活性产生显着影响。与小鼠巨噬细胞相反，IFN-γ以浓度依赖性方式抑制TNF-α刺激的内皮NO合酶活性的诱导。这一观察结果表明，BAEC 和鼠巨噬细胞对 IFN-γ 的反应存在重大差异。本研究的第二个主要目的是确定 IFN-γ 对 BAEC 中 preproET-1 mRNA 表达和 ET-1 分泌率的影响。当测量 8 小时时，单独的 IFN-γ 对 ET-1 mRNA 水平和基础 ET 释放几乎没有影响或没有影响。然而，与 IFN-γ 共同治疗增强了 TNF-α 对 BAEC ET-1 mRNA 转录水平和 ET 释放的刺激作用。相反，用 IFN-γ 预处理细胞 16-24 小时会减弱 TNF-α 的刺激作用。这些发现表明，血管活性介质的内皮细胞表达通过至少两种免疫介质（IFN-γ和TNF-α）的时间相互作用而改变。
Given the pivotal role suggested for IFN-gamma in immune diseases of the vascular wall, we investigated the effects of IFN-gamma on nitric oxide (NO) and endothelin-I (ET-1) expression in bovine aortic endothelial cells (BAEC). We have previously reported that TNF-alpha enhanced NO synthase activity in BAEC as assessed by quantifying release of bioactive NO with reporter monolayers and measuring conversion of L-[C-14]arginine to L-[C-14]citrulline. In murine macrophages IFN-gamma synergizes with TNF-alpha or lipopolysaccharide to induce robust increases in calcium-independent NO synthase activity. In this study we have found that IFN-gamma alone failed to have a significant effect on NO synthase activity in BAEC. In contrast to murine macrophages, IFN-gamma inhibited TNF-alpha-stimulated induction of endothelial NO synthase activity in a concentration-dependent manner. This observation suggests that there is major difference in the response of BAEC and murine macrophages to IFN-gamma.A second major aim of this study was to determine the effect of IFN-gamma on preproET-1 mRNA expression and ET-1 secretion rates in BAEC. IFN-gamma alone had little or no effect on ET-1 mRNA levels and basal ET release when measured for 8 h. However, cotreatment with IFN-gamma potentiated the stimulatory effect of TNF-alpha on BAEC ET-1 mRNA transcript levels and ET release. In contrast, pretreatment of cells with IFN-gamma for 16-24 h blunted the stimulatory effect of TNF-alpha. These findings suggest that endothelial cell expression of vasoactive mediators is modified by the temporal interplay of at least two immune mediators, IFN-gamma and TNF-alpha.