Flavopiridol inhibits lipopolysaccharide-induced TNF-α production through inactivation of nuclear factor-κB and mitogen-activated protein kinases in the MyD88-dependent pathway

Microbiol Immunol. 2011 Mar;55(3):160-7. doi: 10.1111/j.1348-0421.2010.00304.x.


Flavopiridol is a cyclin-dependent kinase inhibitor and inhibits the growth of various cancer cells. The effect of flavopiridol on lipopolysaccharide (LPS)-induced proinflammatory mediator production was examined in RAW 264.7 macrophage-like cells. Flavopiridol significantly reduced the production of tumor necrosis factor-α and, to a lesser extent, nitric oxide in LPS-stimulated cells. Flavopiridol inhibited the activation of nuclear factor-κB and IκB kinase in response to LPS. Flavopiridol also inhibited the activation of a series of mitogen-activated protein kinases, such as p38, stress-activated protein kinase/c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in response to LPS. However, flavopiridol did not alter the expression of tumor necrosis factor receptor-associated factor 6, myeloid differentiation factor 88 (MyD88) or CD14/toll-like receptor (TLR) 4. Flavopiridol inhibited nitric oxide production induced by a MyD88-dependent TLR2 ligand, but not a MyD88-independent TLR3 ligand. Further, flavopiridol did not alter the phosphorylation of interferon regulatory factor 3 in the MyD88-independent pathway. Therefore, it was suggested that flavopiridol exclusively inhibited the activation of nuclear factor-κB and mitogen-activated protein kinases in the MyD88-dependent pathway. Flavopiridol might be useful for the prevention of LPS-induced inflammatory response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Flavonoids / pharmacology*
  • Gene Expression Regulation, Archaeal / drug effects*
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / metabolism*
  • Macrophages / drug effects
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Myeloid Differentiation Factor 88 / metabolism*
  • NF-kappa B / metabolism*
  • Nitric Oxide / biosynthesis
  • Phosphorylation / drug effects
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Factor 6 / metabolism
  • Toll-Like Receptors / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis*


  • Flavonoids
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Piperidines
  • Protein Kinase Inhibitors
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • alvocidib
  • Mitogen-Activated Protein Kinases