title: The antimycotic drugs itraconazole and terbinafine hydrochloride induce the production of human β-defensin-3 in human keratinocytes.
abstract: The antimicrobial peptide human β-defensin-3 (hBD-3) is produced by epidermal keratinocytes, and exhibits broad killing activity against bacteria or fungi. Prostaglandin D(2) 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 H(2), a precursor of prostaglandin D(2) can be converted to thromboxane A(2). 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 D(2) release from keratinocytes and reduced the release of thromboxane B(2), a thromboxane A(2) 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 D(2) release from keratinocytes. These antimycotic drugs may suppress thromboxane A(2) synthesis and redirect the conversion of prostaglandin H(2) towards prostaglandin D(2). 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.
authors.affiliation: Department of Dermatology, Teikyo University, School of Medicine, 11-1, Kaga-2, Itabashi-Ku, Tokyo, Japan. nmk@med.teikyo-u.ac.jp
authors.forename: Naoko
authors.initials: N
authors.lastname: Kanda
authors.forename: Rui
authors.initials: R
authors.lastname: Kano
authors.forename: Takeko
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D000077291:Terbinafine; D013929:Thromboxane B2 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D017077:Culture Media, Conditioned; C422950:DEFB103A protein, human; D009281:Naphthalenes; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D023083:beta-Defensins; D017964:Itraconazole; D013929:Thromboxane B2; D000077291:Terbinafine; D015230:Prostaglandin D2