Inhibition of a p38/stress-activated protein kinase-2-dependent phosphatase restores function of IL-1 receptor-associate kinase-1 and reverses Toll-like receptor 2- and 4-dependent tolerance of macrophages.
J Immunol
; 171(3): 1456-65, 2003 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-12874238
Pretreatment of macrophages with Toll-like receptor (TLR)2 or TLR4 agonists leads to a stage of cell hyporesponsiveness to a second stimulation with TLR agonists. This tolerance state is accompanied by the repression of IL-1 receptor-associated kinase-1, mitogen-activated protein kinases, and IkappaB phosphorylation and expression of genes encoding proinflammatory cytokines, like IL-1beta and TNF-alpha. In this report, we demonstrated that mucin-like glycoprotein (tGPI-mucin) of Trypanosoma cruzi trypomastigotes (TLR2 agonist) and LPS (TLR4 agonist) induce cross-tolerance in macrophages and we addressed the role of phosphatase activity in this process. Analysis of the kinetic of phosphatase activity induced by tGPI-mucin or LPS revealed maximum levels between 12 and 24 h, which correlate with the macrophage hyporesponsiveness stage. The addition of okadaic acid, an inhibitor of phosphatase activity, reversed macrophage hyporesponsiveness after exposure to either LPS or tGPI-mucin, allowing phosphorylation of IL-1R-associated kinase-1, mitogen-activated protein kinases, and IkappaB and leading to TNF-alpha gene transcription and cytokine production. Furthermore, pretreatment with either the specific p38/stress-activated protein kinase-2 inhibitor (SB203580) or the NF-kappaB translocation inhibitor (SN50) prevented the induction of phosphatase activity and hyporesponsiveness in macrophage, permitting cytokine production after restimulation with LPS. These results indicate a critical role of p38/stress-activated protein kinase-2 and NF-kappaB-dependent phosphatase in macrophage hyporesponsiveness induced by microbial products that activate TLR2 and TLR4.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
/
Glicoproteínas de Membrana
/
Macrófagos Peritoneais
/
Monoéster Fosfórico Hidrolases
/
Receptores de Superfície Celular
/
Proteínas Quinases Ativadas por Mitógeno
/
Tolerância Imunológica
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Estados Unidos