Suppression of inducible cyclooxygenase and nitric oxide synthase through activation of peroxisome proliferator-activated receptor-gamma by flavonoids in mouse macrophages.
Peroxisome proliferator-activated receptor (PPAR)gamma transcription factor has been implicated in anti-inflammatory response. Of the compounds tested, apigenin, chrysin, and kaempferol significantly stimulated PPAR gamma transcriptional activity in a transient reporter assay. In addition, these three flavonoids strongly enhanced the inhibition of inducible cyclooxygenase and inducible nitric oxide synthase promoter activities in lipopolysaccharide-activated macrophages which contain the PPAR gamma expression plasmids. However, these three flavonoids exhibited weak PPAR gamma agonist activities in an in vitro competitive binding assay. Limited protease digestion of PPAR gamma suggested these three flavonoids produced a conformational change in PPAR gamma and the conformation differs in the receptor bound to BRL49653 versus these three flavonoids. These results suggested that these three flavonoids might act as allosteric effectors and were able to bind to PPAR gamma and activate it, but its binding site might be different from the natural ligand BRL49653.
Liang
Y C
YC
Institute of Biochemistry, College of Medicine, National Taiwan University, Taipei.
Tsai
S H
SH
Tsai
D C
DC
Lin-Shiau
S Y
SY
Lin
J K
JK
D000818:Animals; D047310:Apigenin; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D017930:Genes, Reporter; D044949:Kaempferols; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011794:Quercetin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*
D005419:Flavonoids; D044949:Kaempferols; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; C043561:chrysin; C006552:kaempferol; D047310:Apigenin; D011794:Quercetin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011451:Prostaglandin-Endoperoxide Synthases