Inhibition of interferon-gamma-induced nitric oxide production in endotoxin-activated macrophages by cytolethal distending toxin.
BACKGROUND
Cytolethal distending toxin (CDT) is a DNA-targeting agent produced by certain pathogenic gram-negative bacteria such as the periodontopathogenic organism Aggregatibacter actinomycetemcomitans. CDT targets lymphocytes and other cells causing cell cycle arrest and apoptosis, impairing the host immune response and contributing to the persistence of infections caused by this microorganism. In this study we explored the effects of CDT on the innate immune response, by investigating how it affects production of nitric oxide (NO) by macrophages.


METHODS
Murine peritoneal macrophages were stimulated with Escherichia coli sonicates and NO production was measured in the presence or not of active CDT.


RESULTS
We observed that CDT promptly and significantly inhibited NO production by inducible nitric oxide synthase (iNOS) in a dose-dependent manner. This inhibition is directed towards interferon-gamma-dependent pathways and is not mediated by either interleukin-4 or interleukin-10.


CONCLUSIONS
This mechanism may constitute an important aspect of the immunosuppression mediated by CDT and may have potential clinical implications in A. actinomycetemcomitans infections.
Fernandes
K P S
KP
Department of Rehabilitation Sciences, Universidade Nove de Julho, São Paulo, Brazil. kristianneporta@terra.com.br
Mayer
M P A
MP
Ando
E S
ES
Ulbrich
A G
AG
Amarente-Mendes
J G P
JG
Russo
M
M
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D029968:Escherichia coli Proteins / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D016166:Free Radical Scavengers / Q000037:antagonists & inhibitors*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D051195:Toll-Like Receptor 2 / Q000187:drug effects
D001427:Bacterial Toxins; D004731:Endotoxins; D029968:Escherichia coli Proteins; D016166:Free Radical Scavengers; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C067044:cytolethal distending toxin; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma