Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B.
J Immunol
; 172(4): 2522-9, 2004 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-14764725
ABSTRACT
Although oxidative stress has been thought to play a general role in the activation of NF-kappaB, the involvement of reactive oxygen species (ROS) in facilitating nuclear translocation of NF-kappaB in neutrophils has not been described. In addition, the mechanisms by which ROS modulate the transcriptional activity of NF-kappaB in response to Toll-like receptor 4 (TLR4)-dependent signaling are not well characterized. To examine these issues, oxidant-dependent signaling events downstream of TLR4 were investigated in neutrophils stimulated with LPS. Pretreatment of neutrophils with the antioxidants N-acetylcysteine or alpha-tocopherol prevented LPS-induced nuclear translocation of NF-kappaB. Antioxidant treatment of LPS-stimulated neutrophils also inhibited the production of proinflammatory cytokines (TNF-alpha, macrophage inflammatory protein-2, and IL-1beta), as well as activation of the kinases IkappaB kinase alpha, IkappaB kinase beta, p38, Akt, and extracellular receptor-activated kinases 1 and 2. The decrease in cytoplasmic levels of IkappaBalpha produced by exposure of neutrophils to LPS was prevented by N-acetylcysteine or alpha-tocopherol. Activation of IL-1R-associated kinase-1 (IRAK-1) and IRAK-4 in response to LPS stimulation was inhibited by antioxidants. These results demonstrate that proximal events in TLR4 signaling, at or antecedent to IRAK-1 and IRAK-4 activation, are oxidant dependent and indicate that ROS can modulate NF-kappaB-dependent transcription through their involvement in early TLR4-mediated cellular responses.
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Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
/
NF-kappa B
/
Espécies Reativas de Oxigênio
/
Receptores de Superfície Celular
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos