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

Flavonoids isolated from citrus were evaluated for their ability to affect the inflammation response through suppression of cytokine expression by hum an monocytes. Several polymethoxylated flavones inhibited lipopolysaccharid e-induced monocyte expression of tumor necrosis factor (TNF alpha). Subsequ ent studies centered on the compound 3,5,6,7,8,3',4'-heptamethoxyflavone (H MF) which produced the highest inhibition (IC50 = 5 mu M). HMF was also a p otent inhibitor of macrophage inflammatory protein-1 alpha (MIP-1 alpha) an d interleukin-10 (IL-10) production, but not of IL-1 beta, IL-6, or IL-8 pr oduction. Suppression of TNF alpha production was at the level of mRNA indu ction as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). HMF was also a potent inhibitor of human phosphodiestera se 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, suggest s that the polymethoxylated flavones inhibit cytokine production in part by suppression of phosphodiesterase activity. The ability of HMF to also inhi bit IL-10 production suggests the additional existence of a phosphodiestera se-in dependent mechanism for this compound.