Dalli Jesmond, Montero-Melendez Trinidad, McArthur Simon, Perretti Mauro
William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London London, UK.
Front Pharmacol. 2012 Feb 28;3:28. doi: 10.3389/fphar.2012.00028. eCollection 2012.
It is postulated that peptides derived from the N-terminal region of Annexin A1, a glucocorticoid-regulated 37-kDa protein, could act as biomimetics of the parent protein. However, recent evidence, amongst which the ability to interact with distinct receptors other then that described for Annexin A1, suggest that these peptides might fulfill other functions at variance to those reported for the parent protein. Here we tested the ability of peptide Ac2-26 to induce chemotaxis of human neutrophils, showing that this peptide can elicit responses comparable to those produced by the canonical activator formyl-Met-Leu-Phe (or FMLP). However, whilst disruption of the chemical gradient abolished the FMLP response, addition of peptide Ac2-26 in the top well of the chemotaxis chamber did not affect (10 μM) or augmented (at 30 μM) the neutrophil locomotion to the bottom well, as elicited by 10 μM peptide Ac2-26. Intriguingly, the sole addition of peptide Ac2-26 in the top wells produced a marked migration of neutrophils. A similar behavior was observed when human primary monocytes were used. Thus, peptide Ac2-26 is a genuine chemokinetic agent toward human blood leukocytes. Neutralization strategies indicated that engagement of either the GPCR termed FPR1 or its cognate receptor FPR2/ALX was sufficient to sustain peptide Ac2-26 induced neutrophil migration. Similarly, application of pharmacological inhibitors showed that cell locomotion to peptide Ac2-26 was mediated primarily by the ERK, but not the JNK and p38 pathways. In conclusion, we report here novel in vitro properties for peptide Ac2-26, promoting neutrophil and monocyte chemokinesis; a process that may contribute to accelerate the resolution phase of inflammation. We postulate that the generation of Annexin A1 N-terminal peptides at the site of inflammation may expedite the egress of migrated leukocytes thus promoting the return to homeostasis.
据推测，来自膜联蛋白A1（一种糖皮质激素调节的37 kDa蛋白）N端区域的肽可能作为母体蛋白的模拟物发挥作用。然而，最近的证据表明，这些肽除了能与膜联蛋白A1所描述的不同受体相互作用外，还可能具有与母体蛋白报道的功能不同的其他功能。在这里，我们测试了肽Ac2 - 26诱导人中性粒细胞趋化性的能力，结果表明该肽能引发与经典激活剂甲酰甲硫氨酸 - 亮氨酸 - 苯丙氨酸（或FMLP）产生的反应相当的反应。然而，虽然化学梯度的破坏消除了FMLP反应，但在趋化性小室的上孔中添加肽Ac2 - 26对10 μM肽Ac2 - 26引发的中性粒细胞向底部孔的运动没有影响（10 μM时）或增强了（30 μM时）这种运动。有趣的是，仅在上孔中添加肽Ac2 - 26就导致了中性粒细胞的显著迁移。当使用人原代单核细胞时也观察到了类似的行为。因此，肽Ac2 - 26是一种对人血白细胞真正的化学促动剂。中和策略表明，称为FPR1的GPCR或其同源受体FPR2 / ALX的参与足以维持肽Ac2 - 26诱导的中性粒细胞迁移。同样，药理学抑制剂的应用表明，细胞向肽Ac2 - 26的运动主要由ERK介导，而不是由JNK和p38途径介导。总之，我们在此报告了肽Ac2 - 26的新的体外特性，即促进中性粒细胞和单核细胞的化学运动；这一过程可能有助于加速炎症的消退阶段。我们推测，在炎症部位产生膜联蛋白A1 N端肽可能会加速迁移白细胞的流出，从而促进恢复内环境稳态。
