The polyphenol ellagic acid exerts anti-inflammatory actions via disruption of store-operated calcium entry (SOCE) pathway activators and coupling mediators

Abstract

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 Ca²⁺ handling, in particular, store-operated Ca²⁺ entry (SOCE), a process critical to proper T cell function. We observed that the acute addition of EA-induced Ca²⁺ release with an EC₅₀ of 63 μM. The Ca²⁺ release was significantly attenuated by Xestospongin C, a known inhibitor of the Inositol 1,4,5-trisphosphate receptor (IP₃R) 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 Ca²⁺ release but also diminished the SOCE-mediated Ca²⁺ influx in a dose-dependent manner. This inhibition was confirmed by reduced Mn²⁺ entry rates in the EA-treated cells. The ATP-induced Ca²⁺ entry was also attenuated in EA-treated HEK293 cells transiently transfected with SOCE channel Orai1-myc and ER-sensor stromal interaction molecule (STIM1) (HEK^STIM/Orai). Moreover, EA treatment interfered with the Orai1 and STIM1 coupling by disrupting STIM1 puncta formation in the HEK^STIM/Orai 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 Ca²⁺ 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.

Keywords: Anti-inflammatory; Ellagic acid; Orai; Store-operated calcium entry (SOCE); Stromal interaction molecule (STIM).