Toll-like receptor ligands induce polymorphonuclear leukocyte migration: key roles for leukotriene B4 and platelet-activating factor.
FASEB J
; 24(2): 637-47, 2010 Feb.
Article
em En
| MEDLINE
| ID: mdl-19843712
ABSTRACT
Activation of toll-like receptors (TLRs) and polymorphonuclear leukocyte (PMN) accumulation at infection sites are critical events of host defense. The involvement of leukotriene (LT) B(4) and platelet-activating factor (PAF) in TLR ligand-induced activation of inflammatory cell functions is essentially unknown. Using an in vitro model of human PMN migration through human endothelial cell monolayers, we demonstrate that prototypic ligands of TLR1/2, 2/6, 3, 4, 5, and 7/8 promote PMN migration, an effect markedly inhibited by 3 LTB(4) receptor antagonists (70-80% inhibition at 100 nM compared to vehicle-treated cells), 3 PAF receptor antagonists (20-50% inhibition at 10 nM), 3 LT biosynthesis inhibitors (75-85% inhibition at 100 nM), and 1 cytosolic phospholipase A(2)alpha (cPLA(2)alpha) inhibitor (90% inhibition at 1 microM). Accordingly, selected TLR ligands caused Ser-505-phosphorylation of cPLA(2)alpha and measurable LTB(4) and PAF biosynthesis in the transmigration assay. As negative controls, interleukin-8- and formyl-methionyl-leucyl-phenylalanine-elicited migration in vitro was not inhibited either by an LTB(4) receptor antagonist or by the cPLA(2)alpha inhibitor. Finally, LTB(4) and PAF receptor antagonists inhibited (up to approximately 65% at optimal doses) TLR ligand-induced PMN infiltration in the mouse air-pouch model. These studies unravel the critical involvement of de novo LTB(4) and PAF biosynthesis in PMN migration elicited by TLR ligands.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Ativação de Plaquetas
/
Movimento Celular
/
Leucotrieno B4
/
Receptores Toll-Like
/
Neutrófilos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2010
Tipo de documento:
Article