Capsaicin inhibits Jurkat T-cell activation by blocking calcium entry current I(CRAC).
Capacitative calcium entry (CCE) through stores-operated Ca2+ channels is an absolute requirement for normal activation of T lymphocytes. Organic blockers/inhibitors of the channel(s) that carry the inward Ca2+ current (I(CRAC)) responsible for CCE are few. Here we show that capsaicin, the pungent ingredient of hot chili pepper, blocks receptor-stimulated Ca2+ entry in Jurkat T cells. Indo-1 measurements of intracellular calcium show that capsaicin blocks CCE without affecting release of inositol-1,4,5-trisphosphate-sensitive internal Ca2+ stores with an IC50 of 32 microM. Block of Ca2+ entry by capsaicin is identical whether CCE is evoked by T-cell receptor (TCR) stimulation, heterologous muscarinic M1 receptor stimulation, or via thapsigargin depletion of internal Ca2+ stores. Patch-clamp experiments show that capsaicin rapidly and reversibly blocks I(CRAC) with an identical dose response as seen with indo-1 measurements. The major voltage-gated K+ channel in Jurkat cells, Kv1.3, is also blocked by capsaicin. Although Kv1.3 block may contribute to reducing CCE by changes in membrane potential, block of I(CRAC) is the primary mechanism by which capsaicin reduces CCE. Capsaicin analogs capsazepine and resiniferatoxin also produce inhibition of CCE via block of I(CRAC). Upon application of capsaicin to Jurkat cells in culture we observed an inhibition of interleukin-2 (IL-2) production in response to TCR stimulation. The dose dependence of capsaicin's reduction of IL-2 was comparable with its block of I(CRAC), thereby illustrating the functional relevance of capsaicin's block of lymphocyte CCE. Thus, capsaicin and its numerous analogs may have potential use as immunomodulatory drugs and should be further investigated in models of inflammation and T-cell activation.
Fischer
B S
BS
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Qin
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D
Kim
K
K
McDonald
T V
TV
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D008856:Microscopy, Fluorescence; D018408:Patch-Clamp Techniques; D013601:T-Lymphocytes / Q000187:drug effects*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007202:Indicators and Reagents; D007376:Interleukin-2; D002211:Capsaicin