title: Pertussis toxin and the adenylate cyclase toxin from Bordetella pertussis activate human monocyte-derived dendritic cells and dominantly inhibit cytokine production through a cAMP-dependent pathway.
abstract: Pertussis toxin (PT) and adenylate cyclase toxin (AT) are AB enterotoxins produced by Bordetella pertussis. PT is a powerful mucosal adjuvant whose cellular target and mechanism of action are unknown; however, emerging evidence suggests that dendritic cells (DC) may be a principal adjuvant target of PT. Here, we investigate the mechanism underlying the effects of these toxins on human monocyte-derived DC (MDDC) in vitro. We found that the effects of PT and AT on MDDC, including maturation, are mediated by cyclic adenosine monophosphate (cAMP). In this regard, adenosine 5'-diphosphate-ribosylation-defective derivatives of PT failed to induce maturation of MDDC, whereas dibutyryl-cAMP (d-cAMP) and Forskolin mimic the maturation of MDDC and dominant inhibition of cytokine production induced by these toxins. Also, cAMP-dependent kinase inhibitors blocked the ability of PT, AT, d-cAMP, and Forskolin to activate MDDC. Taken together, these results show that the effects of PT and AT on MDDC are mediated strictly by cAMP.
authors.affiliation: Division of Vaccine Research, Institute of Human Virology, University of Maryland Biotechnology Institute, and Department of Microbiology, University of Maryland School of Medicine, Baltimore 21201, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Bagley
authors.forename: Sayed F
authors.initials: SF
authors.lastname: Abdelwahab
authors.forename: Robert G
authors.initials: RG
authors.lastname: Tuskan
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fouts
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D017951:Antigen Presentation; D001886:Bordetella pertussis / Q000472:pathogenicity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000276:immunology; D037342:Pertussis Toxin / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D015290:Second Messenger Systems; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D037361:Adenylate Cyclase Toxin; D000276:Adjuvants, Immunologic; D016207:Cytokines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000242:Cyclic AMP; D037342:Pertussis Toxin