期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 81, 期 5, 页码 1311-1321出版社
WILEY
DOI: 10.1189/jlb.1106681
关键词
macrophage; PI-3K; calcitriol; vitamin D
1,25-Dihydroxycholecalciferol, also known as 1 alpha,25-dihydroxyvitamin D-3 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.
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