title: Polymethoxylated flavones derived from citrus suppress tumor necrosis factor-alpha expression by human monocytes.
abstract: 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 (TNFalpha). Subsequent studies centered on the compound 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) which produced the highest inhibition (IC50 = 5 microM). HMF was also a potent inhibitor of macrophage inflammatory protein-1alpha (MIP-1alpha) and interleukin-10 (IL-10) production, but not of IL-1beta, IL-6, or IL-8 production. Suppression of TNFalpha 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, suggests that the polymethoxylated flavones inhibit cytokine production in part by suppression of phosphodiesterase activity. The ability of HMF to also inhibit IL-10 production suggests the additional existence of a phosphodiesterase-independent mechanism for this compound.
authors: USDA, Agricultural Research Service, SAA, U.S. Citrus and Subtropical Products Laboratory, 600 Avenue S, NW, Winter Haven, Florida 33881, USA. jamwh@juno.com
authors: J A
authors: JA
authors: Manthey
authors: K
authors: K
authors: Grohmann
authors: A
authors: A
authors: Montanari
authors: K
authors: K
authors: Ash
authors: C L
authors: CL
authors: Manthey
mesh_terms: D002957:Citrus / Q000737:chemistry*; D000242:Cyclic AMP / Q000096:biosynthesis; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D005419:Flavonoids; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C059294:3,3',4',5,6,7,8-heptamethoxyflavone; D000242:Cyclic AMP