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The hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)2D3 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)2D3 is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin β2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)2D3-dependent gene expression. 1,25(OH)2D3 induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)2D3 along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)2D3 induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)2D3 thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.