Antimycotics suppress the Malassezia extract-induced production of CXC chemokine ligand 10 in human keratinocytes.
Malassezia, a lipophilic yeast, exacerbates atopic dermatitis. Malassezia products can penetrate the disintegrated stratum corneum and encounter subcorneal keratinocytes in the skin of atopic dermatitis patients. Type 1 helper T (Th1) cells infiltrate chronic lesions with atopic dermatitis, and antimycotic agents improve its symptoms. We aimed to identify Malassezia-induced chemokines in keratinocytes and examine whether antimycotics suppressed this induction. Normal human keratinocytes were incubated with a Malassezia restricta extract and antimycotics. Chemokine expression was analyzed by enzyme-linked immunosorbent assays and real-time polymerase chain reaction. Signal transducer and activator of transcription (STAT)1 activity was examined by luciferase assays. The tyrosine-phosphorylation of STAT1 was analyzed by western blotting. The M. restricta extract increased the mRNA and protein expression of Th1-attracting CXC chemokine ligand (CXCL)10 and STAT1 activity and phosphorylation in keratinocytes, which was suppressed by a Janus kinase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine suppressed M. restricta extract-induced CXCL10 mRNA and protein expression and STAT1 activity and phosphorylation. These effects were similarly induced by 15-deoxy-Δ-(12,14) -prostaglandin J2 (15d-PGJ2 ), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes. The antimycotic-induced suppression of CXCL10 production and STAT1 activity was counteracted by a lipocalin-type prostaglandin D synthase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine may suppress the M. restricta-induced production of CXCL10 by inhibiting STAT1 through an increase in 15d-PGJ2 production in keratinocytes. These antimycotics may block the Th1-mediated inflammation triggered by Malassezia in the chronic phase of atopic dermatitis.
Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.
Carren S
CS
Hau
Naoko
N
Kanda
Koichi
K
Makimura
Shinichi
S
Watanabe
D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism*; D003881:Dermatomycoses / Q000188:drug therapy*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008290:Malassezia / Q000737:chemistry; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D000935:Antifungal Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015230:Prostaglandin D2
CXC chemokine ligand 10; Malassezia; antimycotic; atopic dermatitis; keratinocyte