Capsaicin inhibits platelet-activating factor-induced cytosolic Ca2+ rise and superoxide production

Platelet-activating factor (PAF) is an important participant in the inflamm atory process. We studied the regulation of PAF activity by capsaicin in hu man promyelocytic leukemia HL-60 cells. Capsaicin inhibited PAF-induced sup eroxide production in a concentration-dependent manner. In addition to PAF, the fMLP- and extracellular ATP-induced superoxide productions were inhibi ted by capsaicin, whereas PMA-induced superoxide production was not affecte d. In the PAF-stimulated cytosolic Ca2+ increase, capsaicin inhibited in pa rticular the sustained portion of the raised Ca2+ level without attenuation of the peak height. In the absence of extracellular Ca2+, the PAF-induced Ca2+ elevation was not inhibited by capsaicin because capsaicin only inhibi ted the Ca2+ influx from the extracellular space. In addition, capsaicin di d not affect PAF-induced inositol 1,4,5-trisphosphate production, suggestin g that phospholipase C activation by PAF is not affected by capsaicin. Stor e-operated Ca2+ entry (SOCE) induced by thapsigargin was inhibited by capsa icin in a concentration-dependent manner. This capsaicin effect was also ob served on thapsigargin-induced Ba2+ and Mn2+ influx. Furthermore, capsaicin 's inhibitory effect on the thapsigargin-induced Ca2+ rise overlapped with that of SK&F96365, an inhibitor of SOCE. Both capsaicin and SK&F96365 also inhibited PAF-induced cytosolic superoxide generation in HL-60 cells differ entiated by all-trans-retinoic acid. Our data suggest that capsaicin exerts its anti-inflammatory effect by inhibiting SOCE elicited via PLC activatio n, which occurs upon PAF activation and results in the subsequent superoxid e production.