Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
FASEB J. 2011 May;25(5):1697-705. doi: 10.1096/fj.10-175687. Epub 2011 Feb 9.
In humans, the antimicrobial peptide LL-37 and leukotriene B(4) (LTB(4)) are important proinflammatory mediators, whereas lipoxin A(4) (LXA(4)) and resolvin E1 (RvE1) possess anti-inflammatory, proresolving properties. Previously, we reported that LTB(4) triggers LL-37 release from human neutrophils (PMNs) and, conversely, that LL-37 promotes LTB(4) production from these cells. Here we show that this effect of LL-37 is mediated via the GPCR FPR2/ALX. LL-37 (5-30 μg/ml) induces intracellular calcium mobilization in a dose-dependent manner, and the signal transduction leading to LTB(4) release involves p38 MAP kinase and phosphorylation of cPLA(2). LXA(4), an endogenous lipid ligand of FPR2/ALX, and a stable LXA(4) analog [benzo-LXA(4)] were ineffective as stimuli at the concentrations of 0.1-10 nM for LTB(4) release from PMNs. Likewise, the BLT1 ligand RvE1, a derivative of eicosapentaenoic acid, inhibited LTB(4)-induced LL-37 production from PMNs at 1-100 nM, whereas chemerin, a peptide ligand of the RvE1 receptor ChemR23, failed to block LTB(4)-induced LL-37 release at the same concentrations. Hence, in human neutrophils, binding of LL-37 to FPR2/ALX promotes LTB(4) production, which can bind to BLT1 and elicit further LL-37 release. This proinflammatory circuit might be inhibited by LXA(4) and RvE(1) acting at FPR2/ALX and BLT1, respectively, leading to dampened mediator release.
在人类中，抗菌肽 LL-37 和白三烯 B(4)（LTB(4)）是重要的促炎介质，而脂氧素 A(4)（LXA(4)）和分辨率 E1（RvE1）则具有抗炎、促解决的特性。此前，我们报道 LTB(4)可触发人中性粒细胞（PMN）释放 LL-37，反之，LL-37 可促进这些细胞产生 LTB(4)。在这里，我们表明 LL-37 的这种作用是通过 GPCR FPR2/ALX 介导的。LL-37（5-30μg/ml）以剂量依赖性方式诱导细胞内钙动员，而导致 LTB(4)释放的信号转导涉及 p38 MAP 激酶和 cPLA(2)的磷酸化。LXA(4)，FPR2/ALX 的内源性脂质配体，以及一种稳定的 LXA(4)类似物[苯并-LXA(4)]，在刺激 PMN 释放 LTB(4)的浓度为 0.1-10 nM 时无效。同样，BLT1 配体 RvE1，一种二十碳五烯酸的衍生物，在 1-100 nM 时抑制 LTB(4)诱导的 PMN 产生的 LL-37，而趋化素，一种 RvE1 受体 ChemR23 的肽配体，在相同浓度下未能阻止 LTB(4)诱导的 LL-37 释放。因此，在人中性粒细胞中，LL-37 与 FPR2/ALX 结合促进 LTB(4)的产生，后者可与 BLT1 结合并引发进一步的 LL-37 释放。这种促炎回路可能被分别作用于 FPR2/ALX 和 BLT1 的 LXA(4)和 RvE(1)抑制，导致介质释放减少。
