Polymethoxylated Flavones Derived from Citrus Suppress Tumor Necrosis Factor-α Expression by Human Monocytes

• Published in: Journal of natural products (Washington, D.C.) Vol. 62; no. 3; pp. 441 - 444
• Main Authors: Manthey, John A, Grohmann, Karel, Montanari, Antonio, Ash, Kevin, Manthey, Carl L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.03.1999; Glendale, AZ American Society of Pharmacognosy
• Subjects: anti-inflammatory agents; Biological and medical sciences; chemical constituents of plants; chemical structure; Citrus; Citrus - chemistry; Cyclic AMP - biosynthesis; flavonoids; Flavonoids - pharmacology; General pharmacology; Humans; In Vitro Techniques; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Medical sciences; medicinal plants; monocytes; Monocytes - drug effects; Monocytes - metabolism; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - biosynthesis; spectral analysis; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; tumor necrosis factors; Human; Ether; Monocyte; Pharmacognosy; Rutaceae; Antiinflammatory agent; Cytokine; Flavonoid; In vitro; Biological activity; Medicinal plant; Citrus; Dicotyledones; Angiospermae; Plant origin; Spermatophyta; Tumor necrosis factor α
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np980431j

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, 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.