Inhibition of store-operated Ca2+ entry channels and K+ channels by caffelic acid phenethylester in T lymphocytes

The increase of cytoplasmic Ca2+ concentration (Delta[Ca2+](c)) in response to antigenic stimulation is a critical step of signals activating immune responses. In addition, the voltage-gated K+ channels (Kv) in T lymphocytes draw attention as an effective target of immune-modulation. Caffeic acid phenethyl ester (CAPE), an active component of propolis, shows strong anti-inflammatory effects and T cell suppression. Although various mechanism have been suggested for the action of CAPE, the effects of CAPE on intracellular Ca2+ signaling and ion channels are unknown. Here we investigated the effects of CAPE on Delta[Ca2+](c), Ca2+- release activiated Ca2+ current (I-CRAC), and Kv current (I-Kv) in Jurkat T cells, and on Ca2+-activated K+ channel current (I-SK4) overexpressed in HEK-293 cells. I-CRAC was induced by dialyzing T cells and Orail/STIM1 overexpressing HEK293 cells with INsP3/BAPTA-containing pipette solution. CAPE concentration-dependendently decreased both T cells receptor (CD3)- and thapsigargin-induced Delta[Ca2+](c). The phosphorylation of PLC gamma(1) by CD3 stimulation was not affected by CAPE. I-CRAC was almost completely blocked by 25 mu M CAPE. CAPE also inhibited the I-Kv and I-SK4. Albeit the strong inhibition of Ca2+ influx via CRAC, the suppression of IL-2 secretion by CAPE was similarly observed in human peripheral T cells when the CRAC pathway was circumvented by ionomycin. Although the unspecifc inhibition of ion channels by CAPE suggested an intriguing mechanism, the effects of CAPE on signaling pathways other than I-CRAC seem to play dominant roles in the immunomodulation by CAPE. (C) 2009 Elsevier B.V. All rights reserved.