title: Primary 1,25-dihydroxyvitamin D3 response of the interleukin 8 gene cluster in human monocyte- and macrophage-like cells.
abstract: Genome-wide analysis of vitamin D receptor (VDR) binding sites in THP-1 human monocyte-like cells highlighted the interleukin 8 gene, also known as chemokine CXC motif ligand 8 (CXCL8). CXCL8 is a chemotactic cytokine with important functions during acute inflammation as well as in the context of various cancers. The nine genes of the CXCL cluster and the strong VDR binding site close to the CXCL8 gene are insulated from neighboring genes by CCCTC-binding factor (CTCF) binding sites. Only CXCL8, CXCL6 and CXCL1 are expressed in THP-1 cells, but all three are up-regulated primary 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) target genes. Formaldehyde-assisted isolation of regulatory elements sequencing analysis of the whole CXCL cluster demonstrated 1,25(OH)2D3-dependent chromatin opening exclusively for the VDR binding site. In differentiated THP-1 cells the CXCL8 gene showed a 33-fold higher basal expression, but is together with CXCL6 and CXCL1 still a primary 1,25(OH)2D3 target under the control of the same genomic VDR binding site. In summary, both in undifferentiated and differentiated THP-1 cells the genes CXCL8, CXCL6 and CXCL1 are under the primary control of 1,25(OH)2D3 and its receptor VDR. Our observation provides further evidence for the immune-related functions of vitamin D.
authors.affiliation: School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Ryynänen
authors.forename: Carsten
authors.initials: C
authors.lastname: Carlberg
mesh_terms: D001665:Binding Sites; D002117:Calcitriol / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000235:genetics* / Q000378:metabolism; D054427:Chemokine CXCL6 / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D005810:Multigene Family; D018167:Receptors, Calcitriol / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: C475829:CXCL1 protein, human; C515503:CXCL6 protein, human; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; D054427:Chemokine CXCL6; D002843:Chromatin; D016209:Interleukin-8; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D002117:Calcitriol