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KMID : 0043320090320010079
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Archives of Pharmacal Research
2009 Volume.32 No. 1 p.79 ~ p.89
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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
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Sohn Dong-Hwan
Kim Hak-Sung
Jin Ying-Lan
Jin Xing-Yu
Hur Jin
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Abstract
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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-α (TNF-α). Treatment of cells with YL-I-108 significantly inhibited LPS-stimulated activator protein-1 (AP-1)-dependent reporter gene expression, whereas nuclear factor-κB (NF-κB) 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.
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KEYWORD
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AP-1, Chalcone, Heme oxygenase-1, Inflammation, Nitric oxide, Nrf2
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