期刊
JOURNAL OF NEUROINFLAMMATION
卷 7, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1742-2094-7-86
关键词
-
资金
- National Science Council, Taiwan
- Chang Gung Medical Research Foundation, Taiwan [NSC97-2321-B-182-007, NSC98-2321-B-182-004, NSC96-2320-B-182-009, CMRPD150253, CMRPD150313, CMRPD170492, CMRPD180372]
Background: Prostaglandin E-2 (PGE(2)), an arachidonic acid metabolite converted by cyclooxygenase-2 (COX-2), plays important roles in the regulation of endothelial functions in response to bacterial infection. The enzymatic activity of COX-2 can be down-regulated by heme oxygenase-1 (HO-1) induction. However, the mechanisms underlying HO-1 modulating COX-2 protein expression are not known. Objective: The aim of the present study was to investigate whether the up-regulation of HO-1 regulates COX-2 expression induced by lipopolysaccharide (LPS), an endotoxin produced by Gram negative bacteria, in mouse brain endothelial cells (bEnd.3) Methods: Cultured bEnd.3 cells were used to investigate LPS-induced COX-2 expression and PGE(2) production. Cobalt protoporphyrin IX (CoPP, an HO-1 inducer), infection with a recombinant adenovirus carried with HO-1 gene (Adv-HO-1), or zinc protoporphyrin (ZnPP, an HO-1 inhibitor) was used to stimulate HO-1 induction or inhibit HO-1 activity. The expressions of COX-2 and HO-1 were evaluated by western blotting. PGE(2) levels were detected by an enzyme-linked immunoassay. Hemoglobin (a chelator of carbon monoxide, CO, one of metabolites of HO-1) and CO-RM2 (a CO releasing molecule) were used to investigate the mechanisms of HO-1 regulating COX-2 expression. Results: We found that LPS-induced COX-2 expression and PGE2 production were mediated through NF-kappa B (p65) via activation of Toll-like receptor 4 (TLR4). LPS-induced COX-2 expression was inhibited by HO-1 induction by pretreatment with CoPP or infection with Adv-HO-1. This inhibitory effect of HO-1 was reversed by pretreatment with either ZnPP or hemoglobin. Pretreatment with CO-RM2 also inhibited TLR4/MyD88 complex formation, NF-kappa B (p65) activation, COX-2 expression, and PGE(2) production induced by LPS. Conclusions: We show here a novel inhibition of HO-1 on LPS-induced COX-2/PGE(2) production in bEnd.3. Our results reinforce the emerging role of cerebral endothelium-derived HO-1 as a protector against cerebral vascular inflammation triggered by bacterial infection.
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