Abstract
Pharmacological agents that can modulate Ca2+ homeostasis are being extensively explored as potential anti‐inflammatory agents. Ellagic acid (EA), a polyphenolic compound found in many fruits and plant extracts, has been known to possess anti‐inflammatory properties. However, the mechanism of action behind its anti‐inflammatory action is unclear. We studied the effects of EA on Ca2+ handling, in particular, store‐operated Ca2+ entry (SOCE), a process critical to proper T cell function. EA is thought to modulate Ca2+ homeostasis by enhancing sarcoplasmic endoplasmic reticulum ATPase pump (SERCA) activity, however effects of EA on Ca2+ signaling is not clearly understood. We demonstrate that acute addition of EA induced Ca2+ release (EC50= 63 μM). A 12 h incubation of Jurkat T cells with EA decreased the ATP‐induced Ca2+ release and diminished the SOCE‐mediated Ca2+ influx in a dose dependent manner (IC50= 23 μM). The inhibition of SOCE was also confirmed by reduced Mn2+ entry rates in the EA‐treated cells. The two important components of SOCE are the endoplasmic reticulum (ER)‐Ca2+ sensor Stromal Interaction Molecule (STIM), and highly‐Ca2+ selective plasma membrane (PM) Orai channels. EA treatment attenuated the ATP‐induced Ca2+ influx in EA‐treated HEK293 cells transiently transfected with SOCE channel Orai1‐myc and ER‐sensor stromal interaction molecule (STIM1) (HEKSTIM/Orai). Furthermore, EA treatment interfered with the Orai1 and STIM1 coupling by disrupting STIM1 puncta formation in the HEKSTIM/Orai cells. Since expression of certain cytokines is directly dependent on Ca2+ influx, we measured the levels of IL‐2 and INFγ in EA‐treated Jurkat cells. Indeed, EA‐treated resulted in a significant decrease in IL‐2 and INFγ expression. The activity of nuclear factor of activated T‐cell (NFAT), a transcriptional factor has been shown to be dependent on SOCE mediated Ca2+ influx. Prolong exposure to EA decreased the translocation of nuclear factor of activated T‐cell in stimulated T cells. Hence, by inhibiting SOCE mediated Ca2+ influx, EA decreased downstream activation of pro‐inflammatory mediators. These observations suggest a novel target to EA‐mediated effects and provide insight into the mechanisms underlying EA mediated anti‐inflammatory effects.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Published Version
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