The antimycotic drugs itraconazole and terbinafine hydrochloride induce the production of human β-defensin-3 in human keratinocytes

The antimicrobial peptide human β-defensin-3 (hBD-3) is produced by epidermal keratinocytes, and exhibits broad killing activity against bacteria or fungi. Prostaglandin D2 enhances hBD-3 production in human keratinocytes by stimulating a transcription factor, activator protein-1 via chemoattractant receptor-homologous molecule expressed on T helper 2 cells (CRTH2). Prostaglandin H2, a precursor of prostaglandin D2 can be converted to thromboxane A2. Certain antimycotic drugs act on keratinocytes and modulate their production of chemokines. In this in vitro study, we examined the effects of antimycotics on hBD-3 production in human keratinocytes. Antimycotics itraconazole and terbinafine hydrochloride increased hBD-3 secretion and mRNA levels in parallel to the enhanced activity of activator protein-1, expression and phosphorylation of activator protein-1 component, c-Fos, but fluconazole was ineffective. These effects were abrogated by CRTH2 antagonist. Itraconazole and terbinafine hydrochloride increased prostaglandin D2 release from keratinocytes and reduced the release of thromboxane B2, a thromboxane A2 metabolite. The conditioned medium from itraconazole or terbinafine hydrochloride-treated keratinocytes inhibited the growth of Candida albicans dependently on hBD-3. These results suggest that itraconazole and terbinafine hydrochloride may enhance c-Fos expression and phosphorylation, activator protein-1 activity and hBD-3 production by increasing prostaglandin D2 release from keratinocytes. These antimycotic drugs may suppress thromboxane A2 synthesis and redirect the conversion of prostaglandin H2 towards prostaglandin D2. The induction of hBD-3 in keratinocytes is another possible mechanism for the antimycrobial effects of these drugs, which may augment the cutaneous defense activity against infection.