Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Originally published online as doi:10.1189/jlb.1207833 on June 17, 2008

Published online before print June 17, 2008
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(Journal of Leukocyte Biology. 2008;84:519-528.)
© 2008 by Society for Leukocyte Biology

Myeloid cell differentiation in response to calcitriol for expression CD11b and CD14 is regulated by myeloid zinc finger-1 protein downstream of phosphatidylinositol 3-kinase

Alireza Moeenrezakhanlou*,{ddagger}, Lindsay Shephard*, Lucia Lam* and Neil E. Reiner*,{dagger},1

* Departments of Medicine (Division of Infectious Diseases) and
{dagger} Microbiology and Immunology, University of British Columbia, Faculties of Medicine and Science, and Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada; and
{ddagger} School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

1 Correspondence: Division of Infectious Diseases, University of British Columbia, Rm. 452D, 2733 Heather St., Vancouver, BC V5Z 3J5, Canada. E-mail: ethan{at}interchange.ubc.ca

Immature cells of the mononuclear phagocyte series differentiate in response to calcitriol. This is accompanied by increased expression of both CD11b and CD14 and has been shown to be phosphatidylinositol 3-kinase (PI3K) dependent. The events downstream of PI3K that regulate mononuclear phagocyte gene expression, however, remain to be fully understood. In the present study, we show that incubation of THP-1 cells with calcitriol brings about activation of the myeloid zinc finger-1 (MZF-1) transcription factor dependent upon PI3K. In addition, we show that the proximal promoter regions of both CD11b and CD14 contain functional MZF-1 binding sites that are calcitriol responsive. Site-directed mutagenesis of the putative MZF-1 elements abolished MZF-1 binding to the promoters of both CD11b and CD14. Not only did calcitriol treatment increase MZF-1 DNA binding activity to these sites, but it also up-regulated cellular levels of MZF-1. Silencing of MZF-1 resulted in a markedly blunted response to calcitriol for induction of both CD11b and CD14 mRNA transcript levels. Cell surface expression of CD11b and CD14 was also reduced, but to a lesser extent. Taken together, these results show that MZF-1 is involved downstream of PI3K in a calcitriol-induced signaling pathway leading to myeloid cell differentiation and activation of CD11b and CD14.

Key Words: MZF-1 • PI3K • THP-1 • transcription factor • 1,25-dihydroxyvitamin D3






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