Mullet D, Fertel R H, Kniss D, Cox G W
Department of Pharmacology, Ohio State University College of Medicine, Columbus 43210, USA.
J Immunol. 1997 Jan 15;158(2):897-904.
Macrophages treated with IFN-gamma alone are stimulated to produce nitric oxide. The level of nitric oxide production can be enhanced significantly when IFN-gamma treatment is combined with other agents (e.g., LPS, TNF-alpha, IL-2, etc.). We tested the hypothesis that cAMP plays a role in the IFN-gamma-induced activation of macrophages. Our experiments indicate that factors that increase the concentration of cAMP in the murine macrophage cell line ANA-1 can also enhance IFN-gamma-induced production of nitric oxide. PGE2 and cholera toxin increased the production of nitrite (an indicator of nitric oxide production) in IFN-gamma-treated ANA-1 macrophages by at least twofold. These factors produced no increase in nitric oxide production in the absence of IFN-gamma treatment. The increase in nitric oxide production corresponded to an increase in the accumulation of nitric oxide synthase mRNA without a change in stability of mRNA. Dibutyryl cAMP and Sp-cAMPs (a selective activator of cAMP-dependent protein kinase I and II) also increased nitric oxide production in IFN-gamma-treated macrophages. However, at very high concentrations (i.e., >100 microM), the stimulatory effect was decreased. These studies indicate that elevation of intracellular cAMP causes a dose-dependent, biphasic alteration of IFN-gamma-induced nitric oxide production in murine macrophages. Moreover, they suggest that agents that affect nitric oxide synthesis may do so via modulation of the cAMP second messenger system.
单独用γ干扰素处理巨噬细胞可刺激其产生一氧化氮。当γ干扰素处理与其他因子（如脂多糖、肿瘤坏死因子-α、白细胞介素-2等）联合使用时，一氧化氮的产生水平可显著提高。我们检验了环磷酸腺苷（cAMP）在γ干扰素诱导的巨噬细胞活化中起作用这一假说。我们的实验表明，能增加小鼠巨噬细胞系ANA-1中cAMP浓度的因子也能增强γ干扰素诱导的一氧化氮产生。前列腺素E2和霍乱毒素使经γ干扰素处理的ANA-1巨噬细胞中亚硝酸盐（一氧化氮产生的指标）的产生至少增加了两倍。在未用γ干扰素处理的情况下，这些因子不会使一氧化氮产生增加。一氧化氮产生的增加与一氧化氮合酶mRNA积累的增加相对应，而mRNA的稳定性没有变化。二丁酰环磷酸腺苷和Sp-cAMPs（一种环磷酸腺苷依赖性蛋白激酶I和II的选择性激活剂）也增加了经γ干扰素处理的巨噬细胞中一氧化氮的产生。然而，在非常高的浓度（即>100微摩尔）时，刺激作用减弱。这些研究表明，细胞内cAMP水平的升高会导致小鼠巨噬细胞中γ干扰素诱导的一氧化氮产生呈剂量依赖性的双相变化。此外，它们提示影响一氧化氮合成的因子可能是通过调节环磷酸腺苷第二信使系统来实现的。
