Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 36, Issue 1, Pages 133-140Publisher
KARGER
DOI: 10.1159/000374058
Keywords
CD4(+) T cells; Chloroquine; Transient receptor potential C3 (TRPC3); IP3 receptor; Thapsigargin
Categories
Funding
- 973 Research Program [2011CB809100]
- National Natural Science Foundation of China [31140087, 30971514, 30900816, 31371307]
- Natural Science Foundation of Hubei Province [2014CFC1116]
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Background/Aims: Bitter-tasting chloroquine can suppress T cell activation by inhibiting Ca2+ signaling. However, the mechanism of inhibition remains largely unclear. Methods: In this study, CD4(+) T cells were isolated from the thymus, and the calcium content of CD4(+) thymocytes was measured using fura-2 AM and a TILL imaging system. Pyrazole-3 (Pyr3), thapsigargin (TG), and caffeine were used to assess the effects of chloroquine on the intracellular Ca2+ content of CD4(+) T cells. Results: In murine CD4(+) thymocytes, chloroquine decreased the TG-triggered intracellular Ca2+ increase in a dose-dependent manner. In the absence of chloroquine under Ca2+-free conditions (0 mM Ca2+ and 0.5 mM EGTA), TG induced a transient Ca2+ increase. After restoration of the extracellular Ca2+ concentration to 2 mM, a dramatic Ca2+ increase occurred. This elevation was completely blocked by chloroquine and was markedly inhibited by Pyr3, a selective antagonist of transient receptor potential C3 (TRPC3) channel and stromal interaction molecule (STIM)/Orai channel. Furthermore, the TG-induced transient Ca2+ increase under Ca2+-free conditions was eliminated in the presence of chloroquine. Chloroquine also blocked the dialyzed inositol-1,4,5-trisphosphate (IP3)-induced intracellular Ca2+ increase. However, chloroquine was not able to decrease the caffeine-induced Ca2+ increase. Conclusion: These data indicate that chloroquine inhibits the elevation of intracellular Ca2+ in thymic CD4(+) T cells by inhibiting IP3 receptor-mediated Ca2+ release from intracellular stores and TRPC3 channel-mediated and/or STIM/Orai channel-mediated Ca2+ influx.
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