Capsaicin inhibits Jurkat T-cell activation by blocking calcium entry current I-CRAC

Capacitative calcium entry (CCE) through stores-operated Ca2+ channels is a n absolute requirement for normal activation of T lymphocytes. Organic bloc kers/inhibitors of the channel(s) that carry the inward Ca2+ current (I-CRA C) responsible for CCE are few. Here we show that capsaicin, the pungent in gredient of hot chili pepper, blocks receptor-stimulated Ca2+ entry in Jurk at T cells. Indo-1 measurements of intracellular calcium show that capsaici n blocks CCE without affecting release of inositol-1,4,5-trisphosphate-sens itive internal Ca2+ stores with an IC50 of 32 muM. Block of Ca2+ entry by c apsaicin is identical whether CCE is evoked by T-cell receptor (TCR) stimul ation, heterologous muscarinic M1 receptor stimulation, or via thapsigargin depletion of internal Ca2+ stores. Patch-clamp experiments show that capsa icin rapidly and reversibly blocks I-CRAC with an identical dose response a s seen with indo-1 measurements. The major voltage-gated K+ channel in Jurk at cells, Kv1.3, is also blocked by capsaicin. Although Kv1.3 block may con tribute to reducing CCE by changes in membrane potential, block Of I-CRAC i s the primary mechanism by which capsaicin reduces CCE. Capsaicin analogs c apsazepine and resiniferatoxin also produce inhibition of CCE via block of I-CRAC. Upon application of capsaicin to Jurkat cells in culture we observe d an inhibition of interleukin-2 (IL-2) production in response to TCR stimu lation. 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 anal ogs may have potential use as immunomodulatory drugs and should be further investigated in models of inflammation and T-cell activation.