Lavigne Mark C, Murphy Philip M, Leto Thomas L, Gao Ji-Liang
Laboratory of Host Defenses, NIAID, NIH, Bethesda, MD 20892, USA.
Cell Immunol. 2002 Jul-Aug;218(1-2):7-12. doi: 10.1016/s0008-8749(02)00564-6.
N-Formylypeptides such as fMet-Leu-Phe (fMLF) potently induce superoxide production through NADPH oxidase activation. The receptors that mediate this response have not been defined. Here, we provide definitive proof using a mouse model that formyl peptide receptor (FPR) is a receptor, but not the only receptor, that mediates fMLF-induced oxidase activation. In wild-type (FPR(+/+)) mouse neutrophils, superoxide production is dependent on the concentration of fMLF with an EC(50) of approximately 5 microM and a peak at approximately 50 microM. In contrast, FPR-deficient (FPR(-/-)) mouse neutrophils produced markedly less superoxide with an EC(50) of approximately 50 microM and a peak at approximately 200 microM. Yet, FPR(+/+) and FPR(-/-) neutrophils showed similar oxidase activation kinetics and G(i) protein-dependent pharmacological sensitivities. These results suggested that a second receptor, likely FPR2, mediates superoxide production at high concentrations of fMLF. This less sensitive second pathway may permit continued oxidant generation in response to formyl peptides when FPR is desensitized in high concentrations of the chemotactic gradient.
诸如甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMLF）之类的N-甲酰化肽可通过激活NADPH氧化酶有效诱导超氧化物的产生。介导这种反应的受体尚未明确。在此，我们使用小鼠模型提供了确凿证据，表明甲酰肽受体（FPR）是介导fMLF诱导的氧化酶激活的受体，但不是唯一的受体。在野生型（FPR(+/+)）小鼠中性粒细胞中，超氧化物的产生取决于fMLF的浓度，其半数有效浓度（EC(50)）约为5微摩尔，峰值约为50微摩尔。相比之下，FPR缺陷型（FPR(-/-)）小鼠中性粒细胞产生的超氧化物明显较少，EC(50)约为50微摩尔，峰值约为200微摩尔。然而，FPR(+/+)和FPR(-/-)中性粒细胞显示出相似的氧化酶激活动力学和G(i)蛋白依赖性药理敏感性。这些结果表明，第二种受体可能是FPR2，在高浓度fMLF时介导超氧化物的产生。当FPR在高浓度趋化梯度中脱敏时，这种敏感性较低的第二条途径可能允许对甲酰肽持续产生氧化剂。
