The Polyphenol Ellagic Acid Exerts Anti-inflammatory Actions Via Disruption of Store-operated Calcium Entry (SOCE) Pathway Activators and Coupling Mediators

Ellagic acid, a naturally occurring phenol found in a variety of fruits and nuts has been shown to possess anti-inflammatory properties. However, the mechanism of action behind its anti-inflammatory action is unclear. Using human Jurkat T cells, our study examined the effects of ellagic acid (EA) on Ca handling, in particular, store-operated Ca entry (SOCE), a process critical to proper T cell function. We observed that the acute addition of EA-induced Ca release with an EC of 63 μM. The Ca release was significantly attenuated by Xestospongin C, a known inhibitor of the Inositol 1,4,5-trisphosphate receptor (IPR) channel and was unaffected by the phospholipase C (PLC) inhibitor, U73122. Furthermore, chronic incubation of Jurkat T cells with EA not only decreased the ATP-induced Ca release but also diminished the SOCE-mediated Ca influx in a dose-dependent manner. This inhibition was confirmed by reduced Mn entry rates in the EA-treated cells. The ATP-induced Ca entry was also attenuated in EA-treated HEK293 cells transiently transfected with SOCE channel Orai1-myc and ER-sensor stromal interaction molecule (STIM1) (HEK). Moreover, EA treatment interfered with the Orai1 and STIM1 coupling by disrupting STIM1 puncta formation in the HEK cells. We observed that EA treatment reduced cytokine secretion and nuclear factor of activated T-cell transcriptional activity in stimulated T cells. Hence, by inhibiting SOCE mediated Ca influx, EA decreased downstream activation of pro-inflammatory mediators. These results suggest a novel target for EA-mediated effects and provide insight into the mechanisms underlying EA-mediated anti-inflammatory effects.