Cholera toxin and heat-labile enterotoxin activate human monocyte-derived dendritic cells and dominantly inhibit cytokine production through a cyclic AMP-dependent pathway.
Cholera toxin (CT) and heat-labile enterotoxin (LT) are powerful mucosal adjuvants whose cellular targets and mechanism of action are unknown. There is emerging evidence that dendritic cells (DC) are one of the principal cell types that mediate the adjuvant effects of these toxins in vivo. Here we investigate the effects of CT and LT on the maturation of human monocyte-derived DC (MDDC) in vitro. We found that an enzymatically active A domain is necessary for both CT and LT to induce the maturation of MDDC and that this activation is strictly cyclic AMP (cAMP) dependent. ADP-ribosylation-defective derivatives of these toxins failed to induce maturation of MDDC, whereas dibutyryl-cyclic-3',5'-AMP and Forskolin mimic the maturation of MDDC induced by CT and LT. In addition, an inhibitor of cAMP-dependent kinases, Rp-8-Br-cAMPs, blocked the ability of CT, LT, and Forskolin to activate MDDC. CT, LT, dibutyryl-cyclic-3',5'-AMP, and Forskolin also dominantly inhibit interleukin 12 and tumor necrosis factor alpha production by MDDC in the presence of saturating concentrations of lipopolysaccharide. Taken together, these results show that the effects of CT and LT on MDDC are mediated by cAMP.
Bagley
Kenneth C
KC
Division of Vaccine Research, Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, USA.
Abdelwahab
Sayed F
SF
Tuskan
Robert G
RG
Fouts
Timothy R
TR
Lewis
George K
GK
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology; D001427:Bacterial Toxins / Q000737:chemistry / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication; D002454:Cell Differentiation / Q000187:drug effects; D002772:Cholera Toxin / Q000737:chemistry / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D004768:Enterotoxins / Q000737:chemistry / Q000494:pharmacology*; D029968:Escherichia coli Proteins; D006801:Humans; D018928:Immunity, Mucosal; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D016207:Cytokines; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D005576:Colforsin; D003994:Bucladesine; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli; D000242:Cyclic AMP