title: Suppressive effects of antimycotics on thymic stromal lymphopoietin production in human keratinocytes.
abstract: BACKGROUND
  Thymic stromal lymphopoietin (TSLP) is produced by epidermal keratinocytes, and it induces Th2-mediated inflammation. TSLP expression is enhanced in lesions with atopic dermatitis, and is a therapeutic target. Antimycotic agents improve the symptoms of atopic dermatitis.
  
  
  OBJECTIVE
  The objective of this study was to examine whether antimycotics suppress TSLP expression in human keratinocytes.
  
  
  METHODS
  Normal human keratinocytes were incubated with polyinosinic-polycytidylic acid (poly I:C) plus IL-4 in the presence of antimycotics. TSLP expression was analyzed by ELISA and real time PCR. Luciferase assays were performed to analyze NF-κB activity. IκBα degradation was analyzed by Western blot analysis.
  
  
  RESULTS
  Poly I:C plus IL-4 increased the secretion and mRNA levels of TSLP, which was suppressed by an NF-κB inhibitor, and also enhanced NF-κB transcriptional activities and induced the degradation of IκBα in keratinocytes. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine suppressed the secretion and mRNA expression of TSLP, NF-κB activity, and IκBα degradation induced by poly I:C plus IL-4. These suppressive effects were similarly manifested by 15-deoxy-Δ-(12,14)-PGJ2 (15d-PGJ2), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes and decreased the release of thromboxane B2, a thromboxane A2 metabolite. Antimycotic-induced suppression of TSLP production and NF-κB activity was counteracted by an inhibitor of lipocalin type-prostaglandin D synthase.
  
  
  CONCLUSIONS
  Antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine may suppress poly I:C plus IL-4-induced production of TSLP by inhibiting NF-κB via increasing 15d-PGJ2 production in keratinocytes. These antimycotics may block the overexpression of TSLP in lesions with atopic dermatitis.
authors.affiliation: Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan. carren.hau@gmail.com
authors.forename: Carren S
authors.initials: CS
authors.lastname: Hau
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; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: C477819:15-deoxyprostaglandin J2; D000935:Antifungal Agents; D016207:Cytokines; C508598:IL4 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015847:Interleukin-4; D011070:Poly I-C; D015230:Prostaglandin D2; D000094632:Thymic Stromal Lymphopoietin
keywords: 15-Deoxy-Δ-(12,14)-PGJ(2); 15-deoxy-Δ-(12,14)-prostaglandin J(2); 15d-PGJ(2); AD; ANOVA; Antimycotic; Atopic dermatitis; CRTH2; D prostanoid receptor; DMSO; DP; GAPDH; HPGDS; IKK; IκB; IκB kinase; KBM; Keratinocyte; LPGDS; NEMO; NF-κB; NF-κB essential modifier; PG; PPARγ; RIP1; TAK1; TGF-β activated kinase 1; TNF receptor; TNF receptor-associated death domain; TNF receptor-associated factor; TNFR; TRADD; TRAF; TRIF; TSLP; TXA(2); TXAS; Thymic stromal lymphopoietin; Toll/IL-1 receptor domain-containing adaptor inducing IFN-β; analysis of variance; atopic dermatitis; chemoattractant receptor-homologous molecule expressed on Th2 cells; dimethylsulfoxide; glyceraldehyde-3-phosphate dehydrogenase; hematopoietic prostaglandin D synthase; inhibitory κB; keratinocyte basal medium; lipocalin-type prostaglandin D synthase; peroxisome proliferator-activated receptor γ; poly I:C; polyinosinic–polycytidylic acid; prostaglandin; receptor interacting protein 1; thromboxane A(2); thromboxane A(2) synthase; thymic stromal lymphopoietin