title: Cholera toxin induces a shift from inactive to active cyclooxygenase 2 in alveolar macrophages activated by Mycobacterium bovis BCG.
abstract: Intranasal vaccination stimulates formation of cyclooxygenases (COX) and release of prostaglandin E(2) (PGE(2)) by lung cells, including alveolar macrophages. PGE(2) plays complex pro- or anti-inflammatory roles in facilitating mucosal immune responses, but the relative contributions of COX-1 and COX-2 remain unclear. Previously, we found that Mycobacterium bovis BCG, a human tuberculosis vaccine, stimulated increased release of PGE(2) by macrophages activated in vitro; in contrast, intranasal BCG activated no PGE(2) release in the lungs, because COX-1 and COX-2 in alveolar macrophages were subcellularly dissociated from the nuclear envelope (NE) and catalytically inactive. This study tested the hypothesis that intranasal administration of BCG with cholera toxin (CT), a mucosal vaccine component, would shift the inactive, NE-dissociated COX-1/COX-2 to active, NE-associated forms. The results showed increased PGE(2) release in the lungs and NE-associated COX-2 in the majority of COX-2(+) macrophages. These COX-2(+) macrophages were the primary source of PGE(2) release in the lungs, since there was only slight enhancement of NE-associated COX-1 and there was no change in COX-1/COX-2 levels in alveolar epithelial cells following treatment with CT and/or BCG. To further understand the effect of CT, we investigated the timing of BCG versus CT administration for in vivo and in vitro macrophage activations. When CT followed BCG treatment, macrophages in vitro had elevated COX-2-mediated PGE(2) release, but macrophages in vivo exhibited less activation of NE-associated COX-2. Our results indicate that inclusion of CT in the intranasal BCG vaccination enhances COX-2-mediated PGE(2) release by alveolar macrophages and further suggest that the effect of CT in vivo is mediated by other lung cells.
authors.affiliation: College of Medicine, Florida Atlantic University, Boca Raton, Florida, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Kogiso
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shinohara
authors.forename: C Kathleen
authors.initials: CK
authors.lastname: Dorey
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Shibata
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001500:BCG Vaccine / Q000276:immunology* / Q000494:pharmacology; D002460:Cell Line; D002772:Cholera Toxin / Q000276:immunology* / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000276:immunology / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism*; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000276:immunology*; D009685:Nuclear Envelope / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D001500:BCG Vaccine; D008565:Membrane Proteins; D002772:Cholera Toxin; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone