title: Anti-inflammatory mechanism of action of azithromycin in LPS-stimulated J774A.1 cells.
abstract: 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.
authors: GSK Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, Zagreb HR-10000, Croatia. mihailo.banjanac@glpg.com
authors: Mihailo
authors: M
authors: Banjanac
authors: Vesna
authors: V
authors: Munić Kos
authors: Krunoslav
authors: K
authors: Nujić
authors: Mila
authors: M
authors: Vrančić
authors: Daniela
authors: D
authors: Belamarić
authors: Slaven
authors: S
authors: Crnković
authors: Mario
authors: M
authors: Hlevnjak
authors: Vesna
authors: V
authors: Eraković Haber
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000276:immunology / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000494:pharmacology; D016718:Arachidonic Acid / Q000276:immunology; D017963:Azithromycin / Q000276:immunology / Q000494:pharmacology*; D002460:Cell Line; D015232:Dinoprostone / Q000276:immunology; D015777:Eicosanoids / Q000276:immunology; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors; D007213:Indomethacin / Q000276:immunology / Q000494:pharmacology; D053762:Interleukin-12 Subunit p40 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D017963:Azithromycin; D011451:Prostaglandin-Endoperoxide Synthases; D054513:Group IV Phospholipases A2; D015232:Dinoprostone; D007213:Indomethacin