Polymethoxylated flavones derived from citrus suppress tumor necrosis factor-α expression by human monocytes

Flavonoids isolated from citrus were evaluated for their ability to affect the inflammation response through suppression of cytokine expression by human monocytes. Several polymethoxylated flavones inhibited lipopolysaccharide-induced monocyte expression of tumor necrosis factor (TNFα). Subsequent studies centered on the compound 3,5,6,7,8,3‘,4‘-heptamethoxyflavone (HMF) which produced the highest inhibition (IC50 = 5 μM). HMF was also a potent inhibitor of macrophage inflammatory protein-1α (MIP-1α) and interleukin-10 (IL-10) production, but not of IL-1β, IL-6, or IL-8 production. Suppression of TNFα production was at the level of mRNA induction as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). HMF was also a potent inhibitor of human phosphodiesterase activity and was shown to induce a substantial elevation of cAMP levels in monocytes. The similarity of these results to the inhibition profile of the known phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, sug...