Transgenic mice expressing rabbit C-reactive protein are resistant to endotoxemia.
Transgenic mice expressing rabbit C-reactive protein are resistant to endotoxemia.
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DOI：
10.1073/pnas.94.6.2575
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发表时间：
1997-03
影响因子：
11.1
通讯作者：
D. Xia;D. Samols
中科院分区：
文献类型：
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作者：
D. Xia;D. Samols
C 反应蛋白 (CRP) 是人类的原型急性时相反应物，是在肝脏中合成的，以响应多种炎症刺激。我们已经培育出一系列转基因小鼠，它们通过大鼠磷酸烯醇丙酮酸羧激酶 (PEPCK) 启动子表达兔 CRP，以响应糖异生信号。在这里，我们表明，与 CRP 表达受到抑制的同窝小鼠相比，表达高水平 CRP 的转基因小鼠部分免受细菌脂多糖的致命攻击。在血小板激活因子 (PAF) 和肿瘤坏死因子 α (TNF-α) 加白细胞介素 1β 的联合攻击中观察到了类似的保护作用，但单独使用 TNF-α 则没有。我们进一步证明，尽管 PAF 能够结合 CRP，但 CRP 提供保护的机制可能不涉及 PAF 的隔离。 PAF 的生物无活性前体溶血 PAF 也结合 CRP，但当表达 CRP 的动物同时受到 PAF 和过量溶血 PAF 攻击时，不会使转基因小鼠对 PAF 敏感。这些结果表明 CRP 通过调节宿主防御系统在体内发挥作用。
C-reactive protein (CRP), the prototypic acute-phase reactant in humans, is synthesized in liver in response to a wide variety of inflammatory stimuli. We have generated a line of transgenic mice that express rabbit CRP from the rat phosphoenolpyruvate carboxykinase (PEPCK) promoter in response to gluconeogenic signals. Here we show that transgenic mice expressing high levels of CRP were partially protected from a lethal challenge of bacterial lipopolysaccharide compared with littermates in which CRP expression had been suppressed. Similar protection was observed with challenges from platelet-activating factor (PAF) and the combination of tumor necrosis factor alpha (TNF-alpha) plus interleukin 1beta, but not with TNF-alpha alone. We further demonstrate that although PAF was able to bind CRP, the mechanism by which CRP provides protection probably does not involve sequestration of PAF. The biologically inactive precursor of PAF, lyso-PAF, also bound CRP but did not render the transgenic mice sensitive to PAF when CRP-expressing animals were simultaneously challenged with PAF and an excess of lyso-PAF. These results suggest that CRP functions in vivo by modulating host defense systems.