|Montanari, Antonio - FL DEPT OF CITRUS|
|Ash, Kevin - DEPT OF BIOLOGY, AMGEN|
|Manthey, Carl - DEPT OF BIOLOGY, AMGEN|
Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 13, 1999
Publication Date: N/A
Interpretive Summary: We undertook an evaluation of key dietary components in citrus for their ability to affect the inflammation response. These components are a class of compounds, termed flavonoids, that are also recoverable from citrus processing byproducts. Research has shown that similar dietary compounds impact the various inflammation responses, some of which are central to chronic inflammation as occurs in arthritis. In this study we discovered that several of these citrus flavonoids are potent inhibitors of a critical step in inflammation. These findings provide useful information to the food industry and to the American consumer concerning the potential health benefits of citrus in the diet. These findings also provide useful information to other scientists investigating the biology of inflammation, and to those biomedical researchers investigating ways to mitigate this debilitating disease.
Technical Abstract: We undertook an evaluation of flavonoids isolated from citrus 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). Our subsequent studies centered on the compound heptamethoxyflavone (HMF) which had the highest inhibitory activity. 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. Fifty percent inhibition of TNFalpha production was achieved with less than 10 uM HMF. Suppression of TNFalpha production was at the level of mRNA induction as determined by quantitative 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 well characterized phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), suppressed TNFalpha and MIP-1alpha production while having minimal effect on IL-6, IL-8 and IL-1beta expression. In contrast to HMF, IBMX did not suppress IL-10 production. It is concluded that polymethoxylated flavones inhibit cytokine production in part by suppression of phosphodiesterase activity. The ability of HMF to inhibit IL-10 production also suggests the existence of a phosphodiesterase-independent mechanism for this compound.