YL-I-108, a synthetic chalcone derivative, inhibits lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 murine macrophages: involvement of heme oxygenase-1 induction and blockade of activator protein-1.
Chalcones, a group of phenolic compounds, exhibit potent anti-inflammatory properties. In the present study, we synthesized chalcone derivative, YL-I-108 ((E)-1-(2-methoxy-4,6-bis(methoxymethoxy)phenyl)-3-(3-nitrophenyl)prop-2-en-1-one), and examined its effect on the production of pro-inflammatory mediators. Treatment of RAW 264.7 macrophages with YL-I-108 potently inhibited nitrite production stimulated by LPS. YL-I-108 treatment also markedly inhibited expressions of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha). Treatment of cells with YL-I-108 significantly inhibited LPS-stimulated activator protein-1 (AP-1)-dependent reporter gene expression, whereas nuclear factor-kappaB (NF-kappaB) activity was not affected, indicating that down-regulation of iNOS expression by YL-I-108 is attributed by blockade of AP-1. In addition, YL-I-108 treatment led to an increase in heme oxygenase-1 (HO-1) mRNA and protein expression, accompanied with the increased expression of nuclear factor-erythroid 2-related factor 2 (Nrf2). Treatment with SnPP, a selective HO-1 inhibitor, reversed YL-I-108-mediated suppression of nitrite production, suggesting that HO-1 induction is implicated in the suppression of NO production by YL-I-108. In contrast, SnPP treatment did not reverse YL-I-108-mediated suppression of AP-1 activation, suggesting that AP-1 inhibition by YL-I-108 is independent of HO-1 induction. Together, these results indicate that YL-I-108 suppresses NO production in LPS-stimulated macrophages via simultaneous induction of HO-1 expression and blockade of AP-1 activation.
Park
Pil-Hoon
PH
Institute of Pharmaceutical Research and Development, Wonkwang University, Jeonbuk, Korea.
Kim
Hak Sung
HS
Hur
Jin
J
Jin
Xing Yu
XY
Jin
Ying Lan
YL
Sohn
Dong Hwan
DH
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C538718:1-(2-methoxy-4,6-bis(methoxymethoxy)phenyl)-3-(3-nitrophenyl)prop-2-en-1-one; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D008665:Metalloporphyrins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D011524:Protoporphyrins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D002599:Chalcone; C032628:tin protoporphyrin IX; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse