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Published online before print February 27, 2007

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(Journal of Leukocyte Biology. 2007;81:1311-1321.)
© 2007 by Society for Leukocyte Biology

1,25-Dihydroxycholecalciferol activates binding of CREB to a CRE site in the CD14 promoter and drives promoter activity in a phosphatidylinositol-3 kinase-dependent manner

Alireza Moeenrezakhanlou^*,, Devki Nandan^*, Lindsay Shephard^* and Neil E. Reiner^*,,1

^* Departments of Medicine (Division of Infectious Diseases) and
Microbiology and Immunology, University of British Columbia, Faculties of Medicine and Science, and Vancouver Coastal Health Research Institute (VCHRI), Vancouver, British Columbia, Canada; and
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, Canada, V5Z 3J5. E-mail: ethan{at}interchange.ubc.ca

1,25-Dihydroxycholecalciferol, also known as 1,25-dihydroxyvitamin D₃ or calcitriol, regulates the differentiation and functional properties of mononuclear phagocytes. Many of these effects involve nongenomic signaling pathways, which are not fully understood. Activation of CD14 expression, a monocyte differentiation marker and coreceptor with TLR-2 for bacterial LPS, by calcitriol was shown previously to be PI-3K-dependent [¹ ]; however, the mechanism of gene activation remained undefined. Using a transcription factor-binding array screen coupled with EMSA, we found evidence for PI-3K-dependent activation of CREB in THP-1 cells incubated with calcitriol. Furthermore, analysis of the proximal promoter of human CD14 identified regions that contained up to seven sequences, which showed significant similarity to a canonical CRE sequence, 5'-TGACGTCA-3'. Treatment of THP-1 cells with calcitriol activated CREB binding to one of these regions at Positions –37 to –55, relative to the transcription start site in a PI-3K-dependent manner. This 19-mer region also became transcriptionally active in a reporter assay in response to calcitriol, again dependent on PI-3K. Mutation of the CRE within the 19-mer abolished this activity. Taken together, these results show that calcitriol signaling, leading to activation of the CD14 promoter, involves CREB activation downstream of PI-3K.

Key Words: macrophage • PI-3K • calcitriol • vitamin D

This article has been cited by other articles:

				A. Moeenrezakhanlou, L. Shephard, L. Lam, and N. E. Reiner 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 J. Leukoc. Biol., August 1, 2008; 84(2): 519 - 528. [Abstract] [Full Text] [PDF]