Immunomodulatory activity of punicalagin, punicalin, and ellagic acid differs from the effect of pomegranate peel extract
Abstract: Background: Our recent study has shown that pomegranate peel extract (PEx) showed
significant immunomodulatory activity, which might be caused by ellagitannins. The aim of this
work was to test the hypothesis that ellagitannin components act synergistically in the modulation of
cytokine production. Methods: Human peripheral blood mononuclear cells (PBMCs) from healthy
donors were stimulated with phytohemagglutinin and treated with different concentrations of
PEx or punicalagin (PG), punicalin (PN), and ellagic acid (EA), alone or with their combinations.
Cytotoxicity, cell proliferation, and cytokine production were determined. Results: Non-cytotoxic
concentrations of all compounds significantly inhibited cell proliferation. IC50 values (µg/mL) were:
EA (7.56), PG (38.52), PEx (49.05), and PN (69.95). PEx and all ellagitannins inhibited the levels of
TNF-α, IL-6, and IL-8, dose-dependently, and their combinations acted synergistically. PEx and all
ellagitannins inhibited Th1 and Th17 responses, whereas the lower concentrations of PEx stimulated
the production of IL-10, a Treg cytokine, as did lower concentrations of EA. However, neither
component of ellagitannins increased Th2 response, as was observed with PEx. Conclusions: The
combination of PG, PN, and EA potentiated the anti-inflammatory response without any significant
synergistic down-modulatory effect on T-cell cytokines. The increased production of IL-10 observed
with PEx could be attributable to EA, but the examined ellagitannins are not associated with the
stimulatory effect of PEx on Th2 response.