Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 76, Issue 5, Pages 1057-1065Publisher
WILEY
DOI: 10.1189/jlb.0404259
Keywords
cyclosporin A; bone marrow; neutrophil granulocytes; megakaryocytes; proliferation
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The calcineurin-dependent, cyclosporin A (CsA)-sensitive transcription factor nuclear factor of activated T cells (NFAT) represents a group of proteins, which is well-characterized as a central regulatory element of cytokine expression in activated T cells. In contrast, little is known about the expression or function of NFAT family members in myeloid cells; moreover, it is unclear whether they are expressed by hematopoietic stem/ progenitor cells. Here, we show that NFATc2 (NFAT1) is expressed at high levels in CD34(+) cells and megakaryocytes but not in cells committed to the neutrophilic, monocytic, or erythroid lineages. Cytokine-induced in vitro differentiation of CD34(+) cells into neutrophil granulocytes results in the rapid suppression of NFATc2 RNA and protein. NFATc2 dephosphorylation/rephosphorylation as well as nuclear/cytoplasmic translocation in CD34(+) cells follow the same calcineurin-dependent pattern as in T lymphocytes, suggesting that NFATc2 activation in these cells is equally sensitive to inhibition with CsA. Finally, in vitro proliferation, but not differentiation, of CD34(+) cells cultured in the presence of fms-like tyrosine kinase 3 ligand (FLT3L), stein cell factor, granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-3, and G-CSF is profoundly inhibited by treatment with CsA in a dose-dependent manner. These results suggest a novel and unexpected role for members of the NFAT transcription factor family in the hematopoietic system.
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