title: Pimecrolimus enhances TLR2/6-induced expression of antimicrobial peptides in keratinocytes.
abstract: Calcineurin inhibitors are potent inhibitors of T-cell-receptor mediated activation of the adaptive immune system. The effects of this class of drug on the innate immune response system are not known. Keratinocytes are essential to innate immunity in skin and rely on toll-like receptors (TLRs) and antimicrobial peptides to appropriately recognize and respond to injury or microbes. In this study we examined the response of cultured human keratinocytes to pimecrolimus. We observed that pimecrolimus enhances distinct expression of cathelicidin, CD14, and human beta-defensin-2 and beta-defensin-3 in response to TLR2/6 ligands. Some of these responses were further enhanced by 1,25 vitamin D3. Pimecrolimus also increased the functional capacity of keratinocytes to inhibit growth of Staphylococcus aureus and decreased TLR2/6-induced expression of IL-10 and IL-1beta. Furthermore, pimecrolimus inhibited nuclear translocation of NFAT and NF-kappaB in keratinocytes. These observations uncover a previously unreported function for pimecrolimus in cutaneous innate host defense.
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, San Diego and VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Büchau
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, San Diego and VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schauber
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hultsch
authors.affiliation: Novartis Institutes for BioMedical Research, Vienna, Austria.
authors.forename: Anton
authors.initials: A
authors.lastname: Stuetz
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, San Diego and VA San Diego Healthcare System, San Diego, California, USA. Electronic address: rgallo@ucsd.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D055666:Lipopeptides; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000378:metabolism*; D023083:beta-Defensins / Q000378:metabolism*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D007166:Immunosuppressive Agents; D055666:Lipopeptides; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009842:Oligopeptides; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D023083:beta-Defensins; C117268:pimecrolimus; C106335:macrophage stimulatory lipopeptide 2; D002117:Calcitriol; D016559:Tacrolimus; D054804:Cathelicidins