Affiliation:
1. Department of Physiology and
2. Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
Abstract
Ca+-dependent signaling regulates the function of dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity. The activity of DCs is suppressed by glucocorticoids, potent immunosuppressive hormones. The present study explored whether the glucocorticoid dexamethasone influences the cytosolic Ca2+concentration ([Ca2+]i) in DCs. To this end, DCs were isolated from mouse bone marrow. According to fura-2 fluorescence, exposure of DCs to lipopolysaccharide (LPS, 100 ng/ml) increased [Ca2+]i, an effect significantly blunted by overnight incubation with 10 nM dexamethasone before LPS treatment. Dexamethasone did not affect the Ca2+content of intracellular stores, sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 and SERCA3 expression, ryanodine receptor (RyR)1 expression, or Ca2+entry through store-operated Ca2+channels. In contrast, dexamethasone increased the transcript level and the membrane protein abundance of the Na+/Ca2+exchanger NCX3. The activity of Na+/Ca2+exchangers was assessed by removal of extracellular Na+in the presence of external Ca2+, a maneuver triggering the Ca2+influx mode. Indeed, Na+removal resulted in a rapid transient increase of [Ca2+]iand induced an outwardly directed current as measured in whole cell patch-clamp experiments. Dexamethasone significantly augmented the increase of [Ca2+]iand the outward current following removal of extracellular Na+. The NCX blocker KB-R7943 reversed the inhibitory effect of dexamethasone on LPS-induced increase in [Ca2+]i. Dexamethasone blunted LPS-induced stimulation of CD86 expression and TNF-α production, an effect significantly less pronounced in the presence of NCX blocker KB-R7943. In conclusion, our results show that glucocorticoid treatment blunts LPS-induced increase in [Ca2+]iin DCs by increasing expression and activity of Na+/Ca2+exchanger NCX3. The effect contributes to the inhibitory effect of the glucocorticoid on DC maturation.
Publisher
American Physiological Society
Cited by
20 articles.
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