title: Suppressive effects of antimycotics on tumor necrosis factor-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes.
abstract: Antimycotic agents are reported to improve cutaneous symptoms of atopic dermatitis or psoriasis vulgaris. Keratinocytes in these lesions excessively produce chemokines, CCL27, CCL2, or CCL5 which trigger inflammatory infiltrates. Tumor necrosis factor-alpha (TNF-alpha) induces production of these chemokines via activating nuclear factor-kappaB (NF-kappaB). We examined in vitro effects of antimycotics on TNF-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes. Antimycotics ketoconazole and terbinafine hydrochloride suppressed TNF-alpha-induced CCL27, CCL2, and CCL5 secretion and mRNA expression in keratinocytes in parallel to the inhibition of NF-kappaB activity while fluconazole was ineffective. Anti-prostaglandin E2 (PGE2) antiserum or antisense oligonucleotides against PGE2 receptor EP2 or EP3 abrogated inhibitory effects of ketoconazole and terbinafine hydrochloride on TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production, indicating the involvement of endogenous PGE2 in the inhibitory effects. Prostaglandin H2, a precursor of PGE2 can be converted to thromboxane A2. Ketoconazole, terbinafine hydrochloride and thromboxane A2 synthase (EC 5.3.99.5) inhibitor, carboxyheptyl imidazole increased PGE2 release from keratinocytes and reduced that of thromboxane B2, a stable metabolite of thromboxane A2. Carboxyheptyl imidazole also suppressed TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production. These results suggest that ketoconazole and terbinafine hydrochloride may suppress TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production by increasing PGE2 release from keratinocytes. These antimycotics may suppress thromboxane A2 synthesis and redirect the conversion of PGH2 toward PGE2. These antimycotics may alleviate inflammatory infiltration in atopic dermatitis or psoriasis vulgaris by suppressing chemokine production.
authors.affiliation: Department of Dermatology, Teikyo University School of Medicine, 11-1, Kaga-2, Itabashi-Ku, Tokyo 173-8605, Japan. nmk@med.teikyo-u.ac.jp
authors.forename: Naoko
authors.initials: N
authors.lastname: Kanda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D054425:Chemokine CCL27; D018946:Chemokine CCL5; D018925:Chemokines / Q000235:genetics*; D019742:Chemokines, CC / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077291:Terbinafine; D013928:Thromboxane A2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; C492276:CCL27 protein, human; C483024:CCL5 protein, human; D018932:Chemokine CCL2; D054425:Chemokine CCL27; D018946:Chemokine CCL5; D018925:Chemokines; D019742:Chemokines, CC; D016328:NF-kappa B; D009281:Naphthalenes; D016376:Oligonucleotides, Antisense; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014409:Tumor Necrosis Factor-alpha; D013928:Thromboxane A2; D000077291:Terbinafine; D015232:Dinoprostone; D007654:Ketoconazole