Role of nuclear factor-kappaB and heme oxygenase-1 in the mechanism of action of an anti-inflammatory chalcone derivative in RAW 264.7 cells.
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 microm) prevents the overproduction of NO in RAW 264.7 macrophages stimulated with lipopolysaccharide (1 microg ml(-1)) due to the inhibition of nuclear factor kappaB (NF-kappaB) activation. We have shown that treatment of cells with CH results in diminished degradation of the NF-kappaB-IkappaB complex leading to inhibition of NF-kappaB 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-kappaB) with a mechanism of action different from antioxidant chalcones.
Alcaraz
María José
MJ
Department of Pharmacology, University of Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjasot, Valencia, Spain. maria.j.alcaraz@uv.es
Vicente
Ana María
AM
Araico
Amparo
A
Dominguez
José N
JN
Terencio
María Carmen
MC
Ferrándiz
María Luisa
ML
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001663:Bilirubin / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D047188:Chalcones; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology*; D051547:Heme Oxygenase-1; D047569:Laser Scanning Cytometry; D008565:Membrane Proteins; D051379:Mice; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D038961:O-Acetyl-ADP-Ribose; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000096:biosynthesis; D015534:Trans-Activators / Q000378:metabolism
C502526:3',4',5',3,4,5-hexamethoxy-chalcone; C449680:3-O-acetyl-ADP-ribose; D000893:Anti-Inflammatory Agents; D047188:Chalcones; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D038961:O-Acetyl-ADP-Ribose; D012333:RNA, Messenger; D015534:Trans-Activators; D009569:Nitric Oxide; D002599:Chalcone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D005978:Glutathione; D001663:Bilirubin