title: IL-4 Downregulates IL-1β and IL-6 and Induces GATA3 in Psoriatic Epidermal Cells: Route of Action of a Th2 Cytokine.
abstract: Clinical improvement of psoriasis induced by IL-4 treatment has been ascribed to changes in dermal inflammatory cells, such as activation of Th2 cells and tolerization of dendritic cells by suppressing IL-23 production. The pathologic epidermal alterations in psoriatic lesional skin include increased epidermal expression of IL-1β, IL-6, S100A7, and human β-defensin 2 (hBD2) and a downregulated expression of the epidermal transcription factor GATA3. Effects of IL-4 on the epidermal compartment of psoriasis lesions were not previously investigated. Therefore, we investigated whether IL-4 directly affects abovementioned psoriatic markers in the epidermal compartment. We cultured freshly isolated psoriatic epidermal cells, whole psoriatic and healthy skin biopsies, human keratinocytes and Langerhans cells with IL-4. The secretion of IL-1β and IL-6 by psoriatic epidermal cells was inhibited by IL-4 via transcriptional and posttranscriptional mechanisms, respectively. In normal skin, IL-4 inhibited IL-1β- and IL-17A-induced hBD2 expression in vitro. In addition, IL-4 reduced the protein expression of hBD2 in psoriatic skin biopsies and induced phospho-STAT6 protein. Epidermal GATA3 mRNA and protein were significantly upregulated by IL-4 in epidermal cells and keratinocytes. Our data argue that IL-4 improves psoriasis not only via modification/induction of Th2 cells and type II dendritic cells, but also via direct inhibition of inflammatory cytokines in resident IL-4R-expressing epidermal cells and thereby alters the psoriatic skin phenotype toward a healthy skin phenotype.
authors.affiliation: Department of Dermatology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands; Department of Immunology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands; a.onderdijk@erasmusmc.nl.
authors.forename: Armanda J
authors.initials: AJ
authors.lastname: Onderdijk
authors.affiliation: Department of Dermatology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands; Department of Immunology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands;
authors.forename: Ewout M
authors.initials: EM
authors.lastname: Baerveldt
authors.affiliation: Department of Cell Biology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands; and.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kurek
authors.affiliation: Department of Dermatology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands; Department of Immunology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands;
authors.forename: Marius
authors.initials: M
authors.lastname: Kant
authors.affiliation: Department of Dermatology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands; Department of Immunology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands;
authors.forename: Edwin F
authors.initials: EF
authors.lastname: Florencia
authors.affiliation: Department of Medical Oncology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.affiliation: Department of Dermatology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands; Department of Immunology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands;
authors.forename: Errol P
authors.initials: EP
authors.lastname: Prens
mesh_terms: D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007801:Langerhans Cells / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; C106641:DEFB4A protein, human; D050990:GATA3 Transcription Factor; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6; D012333:RNA, Messenger; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D050800:STAT6 Transcription Factor; D023083:beta-Defensins; D015847:Interleukin-4; D020932:Nerve Growth Factor