title: Anti-inflammatory activity of structurally related flavonoids, Apigenin, Luteolin and Fisetin.
abstract: Flavonoids are widely distributed in many fruits and plants, and it has been shown that most flavonoids have anti-inflammatory activity; however, the mechanisms of how the flavonoids exhibit their anti-inflammatory activity have not been clarified. We therefore focus on flavonoids Apigenin, Luteolin and Fisetin because of their related structure. We found that these compounds significantly inhibited TNFα-induced NF-κB transcriptional activation; however, they had no effect on the degradation of IκB proteins and the nuclear translocation and DNA binding activity of NF-κB p65. Interestingly, the suppression of NF-κB activation by these flavonoids is due to inhibition of the transcriptional activation of NF-κB, since the compounds markedly inhibited the transcriptional activity of GAL4-NF-κB p65 fusion protein. In addition, while Apigenin and Luteolin slightly inhibited TNFα-induced JNK activation, they had no effect on TNFα-induced activation of ERK and p38. Unexpectedly, Fisetin enhanced and sustained activation of ERK and JNK but not p38 in response to TNFα. Strikingly, TNFα-induced expression of CCL2/MCP-1 and CXCL1/KC was significantly inhibited by Apigenin and Luteolin but not Fisetin. Furthermore, the administration of Apigenin and Luteolin markedly inhibited acute carrageenan-induced paw edema in mice; however, Fisetin failed to have an effect. These observations strongly suggest that the slight structural difference in flavonoids may cause a defective effect of Fisetin on these inflammatory responses, and this may be due to the differences in their direction of the effect on the activation pathways of MAP kinases.
authors: Department of Biochemistry, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. tago-mg@pha.keio.ac.jp
authors: Megumi
authors: M
authors: Funakoshi-Tago
authors: Kei
authors: K
authors: Nakamura
authors: Kenji
authors: K
authors: Tago
authors: Tadahiko
authors: T
authors: Mashino
authors: Tadashi
authors: T
authors: Kasahara
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D047310:Apigenin / Q000494:pharmacology; D002351:Carrageenan / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D020672:I-kappa B Proteins / Q000378:metabolism; D047311:Luteolin / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D041681:NIH 3T3 Cells; D021381:Protein Transport / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D004268:DNA-Binding Proteins; D005419:Flavonoids; D044948:Flavonols; D020672:I-kappa B Proteins; D011993:Recombinant Fusion Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D047310:Apigenin; D002351:Carrageenan; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D047311:Luteolin; C017875:fisetin