Role of nuclear factor‐κB and heme oxygenase‐1 in the mechanism of action of an anti‐inflammatory chalcone derivative in RAW 264.7 cells

• Published in: British journal of pharmacology Vol. 142; no. 7; pp. 1191 - 1199
• Main Authors: Alcaraz, María José, Vicente, Ana María, Araico, Amparo, Dominguez, José N, Terencio, María Carmen, Ferrándiz, María Luisa
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2004; Nature Publishing
• Subjects: 3′,4′,5′,3,4,5‐Hexamethoxy‐chalcone; Biological and medical sciences; heme oxygenase; Medical sciences; NfE2‐related factor; nitric oxide; nuclear factor‐κB; Pharmacology. Drug treatments; heme oxygenase; NfE2-related factor; Enzyme; Antiinflammatory agent; Chalcone; Oxygenase; nuclear factor-κB; Nitric oxide; Heme; 3',4',5',3,4,5-Hexamethoxy-chalcone; Oxidoreductases; Transcription factor NFκB; Mechanism of action
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705821

The synthetic chalcone 3′,4′,5′,3,4,5‐hexamethoxy‐chalcone (CH) is an anti‐inflammatory compound able to reduce nitric oxide (NO) production by inhibition of inducible NO synthase protein synthesis. In this work, we have studied the mechanisms of action of this compound. CH (10–30 μM) prevents the overproduction of NO in RAW 264.7 macrophages stimulated with lipopolysaccharide (1 μg ml−1) due to the inhibition of nuclear factor κB (NF‐κB) activation. We have shown that treatment of cells with CH results in diminished degradation of the NF‐κB–IκB complex leading to inhibition of NF‐κB translocation into the nucleus, DNA binding and transcriptional activity. We also demonstrate the ability of this compound to activate NfE2‐related factor (Nrf2) and induce heme oxygenase‐1 (HO‐1). Our results indicate that CH determines a rapid but nontoxic increase of intracellular oxidative species, which could be responsible for Nrf2 activation and HO‐1 induction by this chalcone derivative.  This novel anti‐inflammatory agent simultaneously induces a cytoprotective response (HO‐1) and downregulates an inflammatory pathway (NF‐κB) with a mechanism of action different from antioxidant chalcones. British Journal of Pharmacology (2004) 142, 1191–1199. doi:10.1038/sj.bjp.0705821