title: IL-17A enhances vitamin D3-induced expression of cathelicidin antimicrobial peptide in human keratinocytes.
abstract: Cathelicidin is strongly expressed in lesional skin in psoriasis and may play an important role as both an antimicrobial peptide and as an autoinflammatory mediator in this chronic skin disease. The mechanism of increased cathelicidin in psoriatic keratinocytes is not known, but recent observations have found that psoriasis has abundant Th17 cells that produce IL-17A and IL-22. We found that human keratinocytes stimulated with supernatants from T cells isolated from lesional psoriatic skin increased expression of cathelicidin when stimulated in the presence of 1,25-dihydroxyvitamin D(3) (1,25D(3)). This increase was signaled through the IL-17RA. In vitro, IL-17A, but not IL-22, enhanced cathelicidin mRNA and peptide expression in keratinocytes dependent on the presence of 1,25D(3). At the same time, coincubation with 1,25D(3) blocked induction of human beta-defensin 2 (HBD2), IL-6, and IL-8, which are other target genes of IL-17A. Act1, an adaptor associated with IL-17RA and essential for IL-17A signaling, mediated cathelicidin induction, as its suppression by small interfering RNA inhibited HBD2 and cathelicidin. Both, 1,25D(3) and IL-17A signaled cathelicidin induction through MEK-ERK. These results suggest that increased IL-17A in psoriatic skin increases cathelicidin through a vitamin D(3)-, Act1-, and MEK-ERK-dependent mechanism. Therapy targeting this cathelicidin-regulating system might be beneficial in patients suffering from psoriasis.
authors.affiliation: Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Peric
authors.forename: Sarah
authors.initials: S
authors.lastname: Koglin
authors.forename: Song-Min
authors.initials: SM
authors.lastname: Kim
authors.forename: Shin
authors.initials: S
authors.lastname: Morizane
authors.forename: Robert
authors.initials: R
authors.lastname: Besch
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Prinz
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schauber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents / Q000096:biosynthesis; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics; D054804:Cathelicidins; D002460:Cell Line; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology*; D015603:Keratinocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology; D011565:Psoriasis / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C508717:IL17A protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D002762:Cholecalciferol