Apigenin: Is It a Pro- or Anti-Inflammatory Agent?

To the Editor-in Chief:

We read with special interest the elegant article by Sawatzky and colleagues1 regarding the involvement of apoptosis-modulating proteins in the resolution of acute inflammation in vivo. One of the findings described by the authors was that in contrast to specific inhibitors of ERK-1/2 proteins, the flavonoid apigenin, which is a nonspecific inhibitor of ERK and Cox-2, actually exacerbated inflammation. Apigenin is a phytopolyphenol widely distributed in the human diet. Like many other flavonoids, apigenin has been reported to exert anti-inflammatory effects such as lowering oxidative stress and preventing the expression of several inflammatory factors, as confirmed by Sawatzky and collaborators.1

We would like to draw attention to the fact that flavonoids are potent anti-inflammatory factors, even when administered after inflammation is settled. Our group has investigated the effect of xanthohumol, a prenylated flavonoid, in nude mice inoculated with human breast cancer MCF7 cells (Soares et al2). Administration of xanthohumol in the mouse’s beverage for 2 months starting 24 hours after inoculation, resulted in dramatic decreases in inflammatory cells, both polymorphonuclear cells and lymphocytes, as compared to vehicle-treated mice. These findings imply that flavonoids prevent inflammation even when administered after the onset of disease.

Corroborating our findings, studies using apigenin and other flavonoids after inflammation has been initiated3,4 have reported anti-inflammatory effects of these flavonoids. Hendriks and colleagues4 examined the effect of another flavonoid compound, luteolin, in lesions of the central nervous system; they observed reduced inflammation and axonal damage when luteolin was administered either before or after disease onset.

Sawatzky and colleagues1 argued that the increase in inflammation they observed after administration of apigenin could be due to inhibition of Cox-2, since Cox-2 inhibitors given at the peak of inflammation resulted in a prolonged inflammatory response. We think that another hypothesis may be applied: flavonoids are potent phytoestrogens and are capable of inducing estrogen-dependent gene transcription, resulting in activation of several tyrosine kinases.5 Estrogens are also able to activate several tyrosine kinase receptors, such as epidermal growth factor receptor and transforming growth factor-β.6,7 Therefore, it is quite possible that flavonoids interact with these signaling pathways as well.

In conclusion, the complexity of the inflammatory process and the variety of flavonoid effects may establish some unpredictability in their interactions. The potential relevance of flavonoids in health justifies the pursuit of this path of investigation.