Induction of heme oxygenase-1 attenuates lipopolysaccharide-induced cyclooxygenase-2 expression in mouse brain endothelial cells

Abstract

BackgroundProstaglandin E2 (PGE2), 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.ObjectiveThe 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)MethodsCultured bEnd.3 cells were used to investigate LPS-induced COX-2 expression and PGE2 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. PGE2 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.ResultsWe found that LPS-induced COX-2 expression and PGE2 production were mediated through NF-κB (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-κB (p65) activation, COX-2 expression, and PGE2 production induced by LPS.ConclusionsWe show here a novel inhibition of HO-1 on LPS-induced COX-2/PGE2 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.

Role of heme oxygenase-1 in inflammatory response induced by mechanical stretch in synovial cells

“…In addition, upregulation of HO-1 in activated macrophages suppressed expression of COX-2, which culminated in the reduction of PGE 2 synthesis [18,36,37]. In the present study, we found that expression levels of the COX-2 and IL-1b genes were significantly suppressed by pretreatment with 50 lM hemin when the HFLS cells were subjected to 10% mechanical stretch (Fig.…”

Inhibitory effect of 9-hydroxy-6,7-dimethoxydalbergiquinol from Dalbergia odorifera on the NF-κB-related neuroinflammatory response in lipopolysaccharide-stimulated mouse BV2 microglial cells is mediated by heme oxygenase-1

“…e l s e v i e r . c o m / l o c a t e / i n t i m p of proinflammatory mediators such as TNF-α, IL-1β, iNOS, COX-2, NO, and PGE 2 [11,12].…”

Asperlin From the Marine-Derived Fungus Aspergillus sp. SF-5044 Exerts Anti-inflammatory Effects Through Heme Oxygenase-1 Expression in Murine Macrophages

“…In addition, HO-1 expression by CoPP exerts anti-inflammatory effects, including down-regulated proinflammatory cytokines and cytoprotective functions in acute lung injury followed by LPS challenge (55). Up-regulation of HO-1 by CoPP significantly inhibited LPS-induced iNOS and COX-2 expression and NO and PGE 2 production in RAW264.7 macrophages (56) and murine bEnd.3 cells (57).…”