Signal pathway involved in inhibition by lipoxin A(4) of production of interleukins induced in endothelial cells by lipopolysaccharide

Objective and design: We examine whether lipoxin A(4) (LXA(4)) inhibits production of interleukins (ILs) in endothelial cells and what signal pathway might participate in the actions of LXA(4). Methods: Cultured pulmonary microvascular endothelial cells (PMVEC) were treated with lipopolysaccharide (LPS), with or without preincubation with LXA(4). Results: The results showed that LPS induced production of IL-I beta, IL-6 and IL-8 in rat PMVEC, upregulated the expressions of myeloid differentiation factor 88 (MyD88), phosphorylated p38 and p42/44 mitogen-activated protein kinase (MAPK), phosphorylated phosphoinositide 3-kinase (PI3-K), DNA-binding activities of nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1). The blockade of p38 MAPK, p42/44 MAPK, PI3-K, NF-kappa B or AP-1 partially inhibited production of IL-1 beta, IL-6 and IL-8 stimulated by LPS, respectively. LXA4 significantly inhibited LPS-stimulated secretion of protein and expressions of mRNA of IL-1 beta, IL-6 and IL-8, activation of p38 MAPK, p42/44 MAPK, PI3-K, NF-kappa B and AP-1 but not MyD88 in PMVEC. Conclusions: LXA4 inhibits synthesis of IL-1 beta, IL-6 and IL-8 in PMVEC and this antagonism is related to PI3-K, p38 and p42/44 MAPK, NF-kappa B and AP-1 pathway-dependent signal transduction.