Signal pathway involved in inhibition by lipoxin A(4) of production of interleukins induced in endothelial cells by lipopolysaccharide.
OBJECTIVE
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-1beta, 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-kappaB) and activator protein-1(AP-1). The blockade of p38 MAPK, p42/44 MAPK, PI3-K, NF-kappaB or AP-1 partially inhibited production of IL-1beta, IL-6 and IL-8 stimulated by LPS, respectively. LXA(4) significantly inhibited LPS-stimulated secretion of protein and expressions of mRNA of IL-1beta, IL-6 and IL-8, activation of p38 MAPK, p42/44 MAPK, PI3-K, NF-kappaB and AP-1 but not MyD88 in PMVEC.


CONCLUSIONS
LXA(4) inhibits synthesis of IL-1beta, IL-6 and IL-8 in PMVEC and this antagonism is related to PI3-K, p38 and p42/44 MAPK, NF-kappaB and AP-1 pathway-dependent signal transduction.
Wu
Sheng-Hua
SH
Department of Pediatrics, Central Laboratory, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, People's Republic of China.
Liao
P-Y
PY
Dong
L
L
Chen
Z-Q
ZQ
D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D007378:Interleukins / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D044045:Lipoxins / Q000494:pharmacology*; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007378:Interleukins; D008070:Lipopolysaccharides; D044045:Lipoxins; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; C040527:lipoxin A4; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases