GSK Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, Zagreb HR-10000, Croatia.
Pharmacol Res. 2012 Oct;66(4):357-62. doi: 10.1016/j.phrs.2012.06.011. Epub 2012 Jul 3.
Azithromycin is a macrolide antibiotic with well-described anti-inflammatory properties which can be attributed, at least partially, to its action on macrophages. We have previously shown, with 18 different macrolide molecules, that IL-6 and PGE₂ inhibition correlates with macrolide accumulation, as well as with their binding to phospholipids in J774A.1 cells. The present study was performed in order to substantiate the hypothesis that biological membranes are a target for macrolide anti-inflammatory activity. By analyzing the effect of azithromycin on overall eicosanoid production, we found that in LPS-stimulated J774A.1 cells, azithromycin, like indomethacin, inhibited the synthesis of all eicosanoids produced downstream of COX. Upstream of COX, azithromycin inhibited arachidonic acid release in the same way as a cPLA₂ inhibitor, while indomethacin had no effect. Further comparison revealed that in LPS-stimulated J774A.1 cells, the cPLA₂ inhibitor showed the same profile of inhibition as azithromycin in inhibiting PGE₂, IL-6, IL-12p40 and arachidonic acid release. Therefore, we propose that the anti-inflammatory activity of azithromycin in this model may be due to interactions with cPLA₂, causing inadequate translocation of the enzyme or disturbing physical interactions with its substrates.
阿奇霉素是一种具有明确抗炎特性的大环内酯类抗生素，其抗炎作用至少部分归因于其对巨噬细胞的作用。我们之前曾用 18 种不同的大环内酯类化合物证明，IL-6 和 PGE₂ 的抑制与大环内酯类化合物的积累以及它们与 J774A.1 细胞中磷脂的结合相关。本研究旨在证实生物膜是大环内酯类抗炎活性的靶标这一假说。通过分析阿奇霉素对整体类花生酸产生的影响，我们发现，在 LPS 刺激的 J774A.1 细胞中，阿奇霉素与吲哚美辛一样，抑制 COX 下游产生的所有类花生酸的合成。在 COX 的上游，阿奇霉素以与 cPLA₂抑制剂相同的方式抑制花生四烯酸的释放，而吲哚美辛则没有作用。进一步的比较表明，在 LPS 刺激的 J774A.1 细胞中，cPLA₂抑制剂在抑制 PGE₂、IL-6、IL-12p40 和花生四烯酸释放方面与阿奇霉素具有相同的抑制谱。因此，我们提出，在这种模型中，阿奇霉素的抗炎活性可能是由于与 cPLA₂的相互作用，导致酶的转位不足或与其底物的物理相互作用受到干扰。
