Abstract
BackgroundChloroquine, a bitter tastant, inhibits Ca2+ signaling, resulting in suppression of B cell activation; however, the inhibitory mechanism remains unclear.ResultsIn this study, thapsigargin (TG), but not caffeine, induced sustained intracellular Ca2+ increases in mouse splenic primary B lymphocytes, which were markedly inhibited by chloroquine. Under Ca2+-free conditions, TG elicited transient Ca2+ increases, which additionally elevated upon the restoration of 2 mM Ca2+. The former were from release of intracellular Ca2+ store and the latter from Ca2+ influx. TG-induced release was inhibited by 2-APB (an inhibitor of inositol-3-phosphate receptors, IP3Rs) and chloroquine, and TG-caused influx was inhibited by pyrazole (Pyr3, an inhibitor of transient receptor potential C3 (TRPC3) and stromal interaction molecule (STIM)/Orai channels) and chloroquine. Moreover, chloroquine also blocked Ca2+ increases induced by the engagement of B cell receptor (BCR) with anti-IgM.ConclusionsThese results indicate that chloroquine inhibits Ca2+ elevations in splenic B cells through inhibiting Ca2+ permeable IP3R and TRPC3 and/or STIM/Orai channels. These findings suggest that chloroquine would be a potent immunosuppressant.
Highlights
Chloroquine, a bitter tastant, inhibits Ca2+ signaling, resulting in suppression of B cell activation; how‐ever, the inhibitory mechanism remains unclear
Chloroquine decreases TG‐induced increases of intracellular Ca2+ In this study, we sought to investigate the effect of chloroquine on intracellular C a2+ in primary B lymphocytes from mouse spleens
The IC50 was 9.3 ± 0.7 mM (Fig. 1c). These results indicate that chloroquine inhibits TG-induced elevations of cytosolic Ca2+
Summary
Chloroquine, a bitter tastant, inhibits Ca2+ signaling, resulting in suppression of B cell activation; how‐ever, the inhibitory mechanism remains unclear. Chloroquine is a bitter tastant [1,2,3,4], which was used to treat malaria [5] and immune-related diseases such as rheumatic disease, systemic lupus erythematosus [6], early-stage AIDS [7] and chronic graft-versus-host disease [8]. It inhibits Ia molecule biosynthesis [9] and CpG DNA-induced protection [10] in B cells. The phosphorylated PLC catalyzes phosphatidylinositol-4, 5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol-1,4,5-trisphosphate
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