Biomol Ther.  2014 Sep;22(5):390-399. 10.4062/biomolther.2014.062.

TI-I-174, a Synthetic Chalcone Derivative, Suppresses Nitric Oxide Production in Murine Macrophages via Heme Oxygenase-1 Induction and Inhibition of AP-1

• Kim MJ
• Kadayat T
• Kim DE
• Lee ES
• Park PH

• KMID: 2380315
• DOI: http://doi.org/10.4062/biomolther.2014.062

Abstract

Chalcones (1,3-diaryl-2-propen-1-ones), a flavonoid subfamily, are widely known for their anti-inflammatory properties. Propenone moiety in chalcones is known to play an important role in generating biological responses by chalcones. In the present study, we synthesized chalcone derivatives structurally modified in propenone moiety and examined inhibitory effect on nitric oxide (NO) production and its potential mechanisms. Among the chalcone derivatives used for this study, TI-I-174 (3-(2-Hydroxyphenyl)-1-(thiophen-3-yl)prop-2-en-1-one) most potently inhibited lipopolysaccharide (LPS)-stimulated nitrite production in RAW 264.7 macrophages. TI-I-174 treatment also markedly inhibited inducible nitric oxide synthase (iNOS) expression. However, TI-I-174 did not significantly affect production of IL-6, cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-alpha), implying that TI-I-174 inhibits production of inflammatory mediators in a selective manner. Treatment of macrophages with TI-I-174 significantly inhibited transcriptional activity of activator protein-1 (AP-1) as determined by luciferase reporter gene assay, whereas nuclear factor-kappaB (NF-kappaB) activity was not affected by TI-I-1744. In addition, TI-I-174 significantly inhibited activation of c-Jun-N-Terminal kinase (JNK) without affecting ERK1/2 and p38MAPK, indicating that down-regulation of iNOS gene expression by TI-I-174 is mainly attributed by blockade of JNK/AP-1 activation. We also demonstrated that TI-I-174 treatment led to an increase in heme oxygenase-1 (HO-1) expression both at mRNA and protein level. Transfection of siRNA targeting HO-1 reversed TI-I-174-mediated inhibition of nitrite production. Taken together, these results indicate that TI-I-174 suppresses NO production in LPS-stimulated RAW 264.7 macrophages via induction of HO-1 and blockade of AP-1 activation.

Keyword

Chalcone; Heme oxygenase-1; Inflammation; Lipopolysaccharide; Nitric oxide

MeSH Terms

Chalcone*
Chalcones
Cyclooxygenase 2
Down-Regulation
Gene Expression
Genes, Reporter
Heme Oxygenase-1*
Inflammation
Interleukin-6
Luciferases
Macrophages*
Nitric Oxide Synthase Type II
Nitric Oxide*
Phosphotransferases
RNA, Messenger
RNA, Small Interfering
Transcription Factor AP-1*
Transfection
Tumor Necrosis Factor-alpha
Chalcone
Chalcones
Cyclooxygenase 2
Heme Oxygenase-1
Interleukin-6
Luciferases
Nitric Oxide
Nitric Oxide Synthase Type II
Phosphotransferases
RNA, Messenger
RNA, Small Interfering
Transcription Factor AP-1
Tumor Necrosis Factor-alpha