Anti-inflammatory activity of structurally related flavonoids, Apigenin, Luteolin and Fisetin

Int Immunopharmacol. 2011 Sep;11(9):1150-9. doi: 10.1016/j.intimp.2011.03.012. Epub 2011 Apr 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Apigenin / pharmacology
  • Carrageenan / pharmacology
  • Cell Line
  • Cell Nucleus / metabolism
  • Chemokine CCL2 / antagonists & inhibitors
  • Chemokine CCL2 / metabolism
  • Chemokine CXCL1 / antagonists & inhibitors
  • Chemokine CXCL1 / metabolism
  • DNA-Binding Proteins / metabolism
  • Edema / chemically induced
  • Edema / drug therapy
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology*
  • I-kappa B Proteins / metabolism
  • Luteolin / pharmacology
  • MAP Kinase Kinase 4 / antagonists & inhibitors
  • MAP Kinase Kinase 4 / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • NIH 3T3 Cells
  • Protein Transport / drug effects
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / metabolism
  • Structure-Activity Relationship
  • Transcription Factor RelA / antagonists & inhibitors
  • Transcription Factor RelA / metabolism
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Inflammatory Agents
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • DNA-Binding Proteins
  • Flavonoids
  • I-kappa B Proteins
  • Recombinant Fusion Proteins
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Apigenin
  • Carrageenan
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Luteolin
  • fisetin