Frequent Calcium Oscillations Lead to NFAT Activation in Human Immature Dendritic Cells

Abstract

Spontaneous Ca2+ oscillations have been reported in certain types of excitable and non-excitable cells. However, the precise molecular mechanism underlying these events and their biological role(s) remain unclear. In the present study we demonstrate for the first time that spontaneous Ca2+ oscillations occur in immature human monocyte-derived dendritic cells and that upon receiving maturation signals via TLRs, the cells lose the high frequency Ca2+ oscillations. We investigated the mechanism and role of the Ca2+ oscillations in immature dendritic cells and found that the inositol-1,4,5-trisphosphate receptor is essential, since oscillations were blocked by pre-treatment of cells with the inositol-1,4,5-trisphosphate receptor antagonist Xestospongin C and 2-APB. A component of the Ca2+ signal is also due to influx from the extracellular environment and may be involved in refilling the intracellular Ca2+ stores. As to their biological role, our results indicate that they are intimately linked to the “immature” phenotype and are associated with the translocation of the transcription factor NFAT into the nucleus. In fact, blocking the Ca2+ oscillations with 2-APB or treating the cells with LPS, leading then to undergo maturation, caused NFAT to remain in the cytoplasm. The results presented in this report provide novel insights into the physiology of immature dendritic cells and into the signaling process(es) controlling their maturation.