Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-kappaB through the suppression of p65 phosphorylation

J Immunol. 2007 Nov 15;179(10):7121-7. doi: 10.4049/jimmunol.179.10.7121.


LPS stimulates monocytes/macrophages through the activation of signaling events that modulate the production of inflammatory cytokines. Apigenin, a flavonoid abundantly found in fruits and vegetables, exhibits anti-proliferative and anti-inflammatory activities through poorly defined mechanisms. In this study, we demonstrate that apigenin inhibits the production of proinflammatory cytokines IL-1beta, IL-8, and TNF in LPS-stimulated human monocytes and mouse macrophages. The inhibitory effect on proinflammatory cytokine production persists even when apigenin is administered after LPS stimulation. Transient transfection experiments using NF-kappaB reporter constructs indicated that apigenin inhibits the transcriptional activity of NF-kappaB in LPS-stimulated mouse macrophages. The classical proteasome-dependent degradation of the NF-kappaB inhibitor IkappaBalpha was observed in apigenin LPS-stimulated human monocytes. Using EMSA, we found that apigenin does not alter NF-kappaB-DNA binding activity in human monocytes. Instead we show that apigenin, as part of a non-canonical pathway, regulates NF-kappaB activity through hypophosphorylation of Ser536 in the p65 subunit and the inactivation of the IKK complex stimulated by LPS. The decreased phosphorylation on Ser536 observed in LPS-stimulated mouse macrophages treated with apigenin was overcome by the over-expression of IKKbeta. In addition, our studies indicate that apigenin inhibits in vivo LPS-induced TNF and the mortality induced by lethal doses of LPS. Collectively, these findings suggest a molecular mechanism by which apigenin suppresses inflammation and modulates the immune response in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apigenin / pharmacology*
  • Cell Line
  • Cytokines / biosynthesis
  • Cytokines / immunology*
  • Humans
  • I-kappa B Kinase / immunology
  • I-kappa B Kinase / metabolism
  • I-kappa B Proteins / immunology
  • I-kappa B Proteins / metabolism
  • Inflammation / chemically induced
  • Inflammation / immunology
  • Inflammation / metabolism
  • Lipopolysaccharides / toxicity*
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Monocytes / immunology*
  • Monocytes / metabolism
  • NF-KappaB Inhibitor alpha
  • Phosphorylation / drug effects
  • Proteasome Endopeptidase Complex / immunology
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Processing, Post-Translational / drug effects*
  • Protein Processing, Post-Translational / immunology
  • Transcription Factor RelA / immunology*
  • Transcription Factor RelA / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / immunology


  • Cytokines
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Apigenin
  • I-kappa B Kinase
  • IKBKB protein, human
  • Ikbkb protein, mouse
  • Proteasome Endopeptidase Complex