title: Bordetella pertussis adenylate cyclase toxin (ACT) induces cyclooxygenase-2 (COX-2) in murine macrophages and is facilitated by ACT interaction with CD11b/CD18 (Mac-1).
abstract: Bordetella pertussis causes a profound inflammatory response in lungs of infected individuals. The adenylate cyclase toxin (ACT) of B. pertussis is a potent enzyme that converts cytosolic ATP into cAMP, and is required for virulence in vivo. During infection, secreted ACT binds to macrophages utilizing the beta2 integrin, Mac-1 (CR3, CD11b/CD18), and subsequent intoxication by ACT inhibits essential antibacterial activities of macrophages. Additionally, Mac-1 has been reported to be a co-receptor for TLR4 required for the full induction of some LPS-responsive genes, including pro-inflammatory cyclooxygenase 2 (COX-2). We have examined the effect of ACT on COX-2 expression in HEK293T cells expressing Mac-1 and in murine macrophages. We report that ACT induces COX-2 in a manner that absolutely requires the catalytic activity of this enzyme and Mac-1 expression dramatically enhanced the sensitivity of cells to ACT-dependent COX-2 induction. The mechanism of COX-2 induction by ACT utilizes the cAMP-PKA-CREB-dependent pathway. Finally, ACT and TLR2 or TLR4 act synergistically to increase COX-2 expression. These data suggest that ACT contributes significantly to the inflammatory response induced by B. pertussis infection by augmenting COX-2 expression and provides evidence against the concept that ACT functions exclusively via its inhibitory effects on phagocytic leucocytes.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), School of Medicine, 660 W. Baltimore Street, Suite 324, Baltimore, MD 21201, USA. dperkins@som.umaryland.edu
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Perkins
authors.forename: Mary C
authors.initials: MC
authors.lastname: Gray
authors.forename: Erik L
authors.initials: EL
authors.lastname: Hewlett
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000378:metabolism*; D000818:Animals; D001886:Bordetella pertussis / Q000378:metabolism* / Q000472:pathogenicity; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004790:Enzyme Induction; D005786:Gene Expression Regulation; D006801:Humans; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology*; D051379:Mice
chemical_list: D037361:Adenylate Cyclase Toxin; D016177:Macrophage-1 Antigen; D051546:Cyclooxygenase 2