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.

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.