Figure 1

Differential activation of NFATc in myeloid cells. Schematic representation of the activation and inhibition of NFATc by calcineurin inhibitors in myeloid cells. (A) Inhibition of calcineurin/NFAT signaling by cyclosporine A (CsA) or the NFAT peptide inhibitor, VIVIT, antagonizes Flt3-L-induced development of bone marrow myeloid cells and increases the number and proliferation of myeloid progenitors[12](B) Antigens- and anti-IgE-dependent activation of NFAT2/c1 and up-regulation of COX2 expression and release of PGE2. CsA and the peptide inhibitor of NFAT, VIVIT, both inhibited antigens- and anti-IgE-mediated activation of COX2 and PGE2 in human neutrophils[45]. (C) LPS activates NFAT3/c4 and NFAT4/c3 in mouse macrophages, and CsA and VIVIT both induced significant inhibition of the LPS-induced TNF production[44]. (D) Zymosan and curdlan failed to activate IL-10, COX2, Egr1 and Egr2 expressions regulated by NFAT2/c1 and NFAT4/c3 in CsA-treated and CnB-deficient neutrophils, indicating that the dectin-1 receptor is the upstream activator of calcineurin. C. albicans killing was not affected in NFAT-deficient neutrophils, suggesting that the CnB regulation of antifungal response may occur through an NFAT-independent anti-microbial mechanism[46]. (E) Downexpression of the NFAT2/c1 by silencing RNA (siRNA) impaired the activation of NOD1 induced by UPEC. CsA or the cell permeable 11R-VIVIT inhibited the UPEC-induced NOD1 expression and NOD1-mediated neutrophil functions (migration capacity, phagocytosis, bacterial killing)[47]. DC: Dendritic cell; MΦ: Macrophage; PMN: Polymorphonuclear neutrophil.