Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3.
The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the alpha- and beta-defensins and cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM) -derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of mammalian genomes revealed evolutionary conservation of the VDRE in a short interspersed nuclear element or SINE in the CAMP promoter of primates that was absent in the mouse, rat, and canine genomes. Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in regulation of primate innate immunity.
Gombart
Adrian F
AF
Department of Medicine, Division of Hematology/Oncology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California 90048, USA. gombarta@csmc.edu
Borregaard
Niels
N
Koeffler
H Phillip
HP
D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D001854:Bone Marrow Cells / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D054804:Cathelicidins; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000502:physiology*; D020218:Response Elements
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D016207:Cytokines; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D002762:Cholecalciferol; D002117:Calcitriol