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Published online before print February 27, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1106681

Received for publication November 16, 2006.
Revised January 30, 2007.
Accepted for publication February 1, 2007.

Article

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 ^*@

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

^@ To whom correspondence should be addressed. E-mail: ethan{at}interchange.ubc.ca.

	Abstract

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

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