Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.
The hormonal form of vitamin D(3), 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)(2)D(3) signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)(2)D(3) is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin beta2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)(2)D(3)-dependent gene expression. 1,25(OH)(2)D(3) induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)(2)D(3) along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)(2)D(3) induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)(2)D(3) thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.
Department of Physiology, McGill University, Montreal, Quebec, Canada.
Tian-Tian
TT
Wang
Frederick P
FP
Nestel
Véronique
V
Bourdeau
Yoshihiko
Y
Nagai
Qiuyu
Q
Wang
Jie
J
Liao
Luz
L
Tavera-Mendoza
Roberto
R
Lin
John W
JW
Hanrahan
Sylvie
S
Mader
John H
JH
White
John H
JH
Hanrahan
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D002117:Calcitriol / Q000494:pharmacology*; D054804:Cathelicidins; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D015603:Keratinocytes / Q000276:immunology; D007633:Keratins / Q000235:genetics* / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D009894:Opportunistic Infections / Q000276:immunology / Q000517:prevention & control; D011552:Pseudomonas Infections / Q000276:immunology / Q000517:prevention & control; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000276:immunology; D030181:Vitamin D Response Element / Q000235:genetics; D023083:beta-Defensins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology
D000276:Adjuvants, Immunologic; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C106641:DEFB4A protein, human; D018167:Receptors, Calcitriol; D023083:beta-Defensins; D007633:Keratins; D002117:Calcitriol