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 E2(PGE2) by lung cells, including alveolar macrophages. PGE2plays 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 thatMycobacterium bovisBCG, a human tuberculosis vaccine, stimulated increased release of PGE2by macrophages activatedin vitro; in contrast, intranasal BCG activated no PGE2release 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 PGE2release in the lungs and NE-associated COX-2 in the majority of COX-2+macrophages. These COX-2+macrophages were the primary source of PGE2release 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 forin vivoandin vitromacrophage activations. When CT followed BCG treatment, macrophagesin vitrohad elevated COX-2-mediated PGE2release, but macrophagesin vivoexhibited less activation of NE-associated COX-2. Our results indicate that inclusion of CT in the intranasal BCG vaccination enhances COX-2-mediated PGE2release by alveolar macrophages and further suggest that the effect of CTin vivois mediated by other lung cells.