title: Impairment of lysosomal functions by azithromycin and chloroquine contributes to anti-inflammatory phenotype.
abstract: Azithromycin and chloroquine have been shown to exhibit anti-inflammatory activities in a number of cellular systems, but the mechanisms of these activities have still not been clarified unequivocally. Since both drugs are cationic, accumulate in acidic cellular compartments and bind to phospholipids with a consequent increase in lysosomal pH and induce phospholipidosis, we examined the relevance of these common properties to their anti-inflammatory activities. We compared also these effects with effects of concanamycin A, compound which inhibits acidification of lysosomes. All three compounds increased lysosomal pH, accumulation of autophagic vacuoles and ubiquitinated proteins and impaired recycling of TLR4 receptor with consequences in downstream signaling in LPS-stimulated J774A.1 cells. Azithromycin and chloroquine additionally inhibited arachidonic acid release and prostaglandin E2 synthesis. Therefore, impairment of lysosomal functions by azithromycin and chloroquine deregulate TLR4 recycling and signaling and phospholipases activation and lead to anti-inflammatory phenotype in LPS-stimulated J774A.1 cells.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovica 29, 10000 Zagreb, Croatia. krunoslav.nujic@glpg.com
authors.forename: Krunoslav
authors.initials: K
authors.lastname: Nujić
authors.forename: Mihailo
authors.initials: M
authors.lastname: Banjanac
authors.forename: Vesna
authors.initials: V
authors.lastname: Munić
authors.forename: Denis
authors.initials: D
authors.lastname: Polančec
authors.forename: Vesna
authors.initials: V
authors.lastname: Eraković Haber
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D017963:Azithromycin / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018942:Macrolides; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; C036978:concanamycin A; D017963:Azithromycin; D002738:Chloroquine; D006180:Proton-Translocating ATPases; D015232:Dinoprostone