Potential Therapeutic Anti-Inflammatory and Immunomodulatory Effects of Dihydroflavones, Flavones, and Flavonols

Abstract

Systemic inflammation, circulating immune cell activation, and endothelial cell damage play a critical role in vascular pathogenesis. Flavonoids have shown anti-inflammatory effects. In this study, we investigated the effects of different flavonoids on the production of pro-inflammatory interleukin (IL) 1β, 6, and 8, and tumor necrosis factor α (TNF-α), in peripheral blood cells. Methods: We studied the whole blood from 36 healthy donors. Lipopolysaccharide (LPS)-stimulated (0.5 μg/mL) whole-blood aliquots were incubated in the presence or absence of different concentrations of quercetin, rutin, naringenin, naringin, diosmetin, and diosmin for 6 h. Cultures were centrifuged and the supernatant was collected in order to measure IL-1β, TNF-α, IL-6, and IL-8 production using specific immunoassay techniques. This production was significantly inhibited by quercetin, naringenin, naringin, and diosmetin, but in no case by rutin or diosmin. Flavonoids exert different effects, maybe due to the differences between aglycons and glucosides present in their chemical structures. However, these studies suggest that quercetin, naringenin, naringin, and diosmetin could have a potential therapeutic effect in the inflammatory process of cardiovascular disease.

Keywords: IL-1β; IL-6; IL-8; TNF-α; aglycons; flavonoids; glycosides; pro-inflammatory cytokines.

Figure 1

Cytokine production curves in lipopolysaccharide (LPS)-stimulated whole blood. One milliliter of whole blood was incubated in the presence of LPS (0.5 μg/mL) in darkness and continuously shaken at 37 °C. The supernatant concentrations of interleukin (IL)-1β, tumor necrosis factor α (TNF-α), IL-6, and IL-8 were measured by ELISA at 0, 4, 6, 8, and 24 h of culture. The diamonds and vertical segments represent the mean ± SEM of six different donors. * p < 0.05 represents a significant difference each time the measurement was compared to baseline production.

Figure 2

Effects of different flavonoids on the production of IL-1β in LPS-stimulated (0.5 μg/mL) whole blood after 6 h of culture. The different panels show the results of the effects of quercetin (A), rutin (B), naringenin (C), naringin (D), diosmetin (E), and diosmin (F). All data are expressed as the mean (top segment of the rectangles) ± SEM (vertical segment) of thirty independent experiments. * p < 0.05: significantly different when compared to the LPS control. δp < 0.05: significantly different when compared to the rhein control.

Figure 3

Effects of different flavonoids on the production of TNF-α in LPS-stimulated (0.5 μg/mL) whole blood after 6 h of culture. The different panels show the results of the effects of quercetin (A), rutin (B), naringenin (C), naringin (D), diosmetin (E), and diosmin (F). All data are expressed as the mean (top segment of the rectangles) ± SEM (vertical segment) of thirty independent experiments. * p < 0.05: significantly different when compared to the LPS control.

Figure 4

Effects of different flavonoids on the production of IL-6 in LPS-stimulated (0.5 μg/mL) whole blood after 6 h of culture. The different panels show the results of the effects of quercetin (A), rutin (B), naringenin (C), naringin (D), diosmetin (E), and diosmin (F). All data are expressed as the mean (top segment of the rectangles) ± SEM (vertical segment) of thirty independent experiments. * p < 0.05: significantly different when compared to the LPS control.

Figure 5

Effects of different flavonoids on the production of IL-8 in LPS-stimulated (0.5 μg/mL) whole blood after 6 h of culture. The different panels show the results of the effects of quercetin (A), rutin (B), naringenin (C), naringin (D), diosmetin (E), and diosmin (F). All data are expressed as the mean (top segment of the rectangles) ± SEM (vertical segment) of thirty independent experiments. * p < 0.05: significantly different when compared to the LPS control.

Figure 6

Chemical structure of flavonoids: (A) Quercetin, (B) rutin, (C) diosmetin, (D) diosmin, (E) naringenin, and (F) naringin.