Chloroquine Inhibits Ca2+ Signaling in Murine CD4+ Thymocytes

Xu, Jianhong; Peng, Yong; Wei, Ming Yu; Wu, Yi; Guo, Dan; Qin, Gangjian; Ji, Guangju; Shen, Jinhua; Liu, Qing Hua

doi:10.1159/000374058

Cited by 12 publications

(14 citation statements)

References 35 publications

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“…These data indicate that TG-induced intracellular Ca 2+ elevations were mediated by above described ion channels, and which will be inhibited by chloroquine and then resulting in decreases. These results are consistent with previous findings that chloroquine blocks TRPC3 and/or STIM/Orai channels resulting in decreases in Ca 2+ levels in smooth muscle cells [1, 3] and in murine CD4 + thymocytes [4]. In addition, BCR engagement frequently occurs in vivo, which then results in immunological responses.…”

Section: Discussionsupporting

confidence: 93%

“…2, we then studied the underlying mechanism. In previous studies, it has been found that chloroquine blocked TRPC3 and/or STIM/Orai channels, resulting in decreases of Ca 2+ in airway smooth muscle cells [3, 18] and in murine CD4 + thymocytes [4]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 90%

“…Chloroquine is a bitter tastant [1–4], 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]. Moreover, it inhibits Ia molecule biosynthesis [9] and CpG DNA-induced protection [10] in B cells.…”

Section: Introductionmentioning

confidence: 99%

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Chloroquine inhibits Ca2+ permeable ion channels-mediated Ca2+ signaling in primary B lymphocytes

Zhao

Luo

et al. 2017

Cell Biosci

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 90%

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Chloroquine inhibits Ca2+ permeable ion channels-mediated Ca2+ signaling in primary B lymphocytes

Zhao

Luo

et al. 2017

Cell Biosci

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“…Consistent with our results, chloroquine-induced Ca 2+ elevations were mediated by the G protein-PLC-IP 3 -IP 3 receptorCa 2+ release pathway in the tongue and airway smooth muscle (ASM) cells [26,28]. However, in murine CD4 + thymocytes, chloroquine blocked the IP 3 -induced intracellular Ca 2+ increase [29]. Such discrepancy might be due to the tissue difference.…”

Section: Discussionsupporting

confidence: 86%

Chloroquine Increases Glucose Uptake via Enhancing GLUT4 Translocation and Fusion with the Plasma Membrane in L6 Cells

Zhou

Yang

Xiong

et al. 2016

Cell Physiol Biochem

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Background/Aims: Chloroquine can induce an increase in the cellular uptake of glucose; however, the underlying mechanism is unclear. Methods: In this study, translocation of GLUT4 and intracellular Ca²⁺ changes were simultaneously observed by confocal microscope in L6 cells stably over-expressing IRAP-mOrange. The GLUT4 fusion with the plasma membrane (PM) was traced using HA-GLUT4-GFP. Glucose uptake was measured using a cell-based glucose uptake assay. GLUT4 protein was detected by Western blotting and mRNA level was detected by RT-PCR. Results: We found that chloroquine induced significant increases in glucose uptake, glucose transporter GLUT4 translocation to the plasma membrane (GTPM), GLUT4 fusion with the PM, and intracellular Ca²⁺ in L6 muscle cells. Chloroquine-induced increases of GTPM and intracellular Ca²⁺ were inhibited by Gallein (G_βγ inhibitor) and U73122 (PLC inhibitor). However, 2-APB (IP₃R blocker) only blocked the increase in intracellular Ca²⁺ but did not inhibit GTPM increase. These results indicate that chloroquine, via the G_βγ-PLC-IP₃-IP₃R pathway, induces elevation of Ca²⁺, and this Ca²⁺ increase does not play a role in chloroqui-ne-evoked GTPM increase. However, GLUT4 fusion with the PM and glucose uptake were significantly inhibited with BAPTA-AM. This suggests that Ca²⁺ enhances GLUT4 fusion with the PM resulting in glucose uptake increase. Conclusion: Our data indicate that chloroquine via G_βγ-PLC-IP₃-IP₃R induces Ca²⁺ elevation, which in turn promotes GLUT4 fusion with the PM. Moreover, chloroquine can enhance GLUT4 trafficking to the PM. These mechanisms eventually result in glucose uptake increase in control and insulin-resistant L6 cells. These findings suggest that chloroquine might be a potential drug for improving insulin tolerance in diabetic patients.

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“…33 Previous studies have indicated that CQ (and its analogs) can be immunosuppressive by direct inhibition of T cell activation and proliferation. 34,35 Therefore, in the current investigation, we cannot rule out the possibility that systemic CQ treatment has actions on the thymus that prevents T cell maturation and release in SHR, analogous to thymectomy. 28 In conclusion, our investigation attempted to address the contribution of the innate immune system on the pathogenesis of hypertension, which is an area currently not well understood.…”

Section: Discussionmentioning

confidence: 86%

Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

McCarthy

Goulopoulou

Baban

et al. 2016

AJHYPE

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Inappropriate immune system activation has been proposed as a unifying mechanism linking the 3 major organ systems that are dysregulated in the development and maintenance of hypertension-the cardiovascular system, the kidneys, and the autonomic nervous system. 1,2 However, the exact mechanisms that initiate this deleterious response, thereby contributing to further increases in blood pressure, are not well understood. 1,2 Although the participation of the adaptive immune system, and specifically T cells, in the pathogenesis of hypertension is not in question, 3,4 there are still gaps surrounding how it is signaled for involvement in the first place.Immune system recognition and response to danger is becoming apparent in a wide range of disease states, including cardiovascular diseases. 5 In this paradigm, the immune system responds to stimuli that it perceives as indicative of danger. 6 As such, molecules released from cell injury and death, called damage-associated molecular patterns (DAMPs), as well as pathogen-associated molecular patterns, signals to the immune system that a response is required. Normally, endogenous molecules are shielded from the immune system via compartmentalization within plasma membranes. However, when a cell dies or undergoes undue stress, these molecules can be released and are able to activate pattern recognition receptors on immune and nonimmune cells. 5 Toll-like receptors (TLR) are a class of innate immune system pattern recognition receptors that recognize and respond to DAMPs. 2,7 We have recently observed that mitochondrial DNA (mtDNA), a DAMP that activates TLR9, is increased in the circulation of spontaneously hypertensive rats (SHR). 8 Specifically, TLR9 recognizes unmethylated cytosine-phosphate-guanine (CpG) dinucleotides and these are common in prokaryotic DNA and mtDNA, but not nuclear DNA. 9 Upon recognition of unmethylated CpG dinucleotides in BACKGROUNDInnate immune system responses to damage-associated molecular patterns (DAMPs) are involved in hypertension. However, the mechanisms of this contribution are not well understood. Circulating mitochondrial DNA is a DAMP that activates Toll-like receptor (TLR) 9 and is elevated in spontaneously hypertensive rats (SHR). Therefore, we hypothesized that lysosomotropic agent chloroquine (CQ) would impair TLR9 signaling, as well as prevent the development of hypertension and immune cell recruitment to the vasculature, in SHR.

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Chloroquine Inhibits Ca2+ Signaling in Murine CD4+ Thymocytes

Cited by 12 publications

References 35 publications

Chloroquine inhibits Ca2+ permeable ion channels-mediated Ca2+ signaling in primary B lymphocytes

Chloroquine inhibits Ca2+ permeable ion channels-mediated Ca2+ signaling in primary B lymphocytes

Chloroquine Increases Glucose Uptake via Enhancing GLUT4 Translocation and Fusion with the Plasma Membrane in L6 Cells

Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

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