title: Influence of Th2 Cytokines on the Cornified Envelope, Tight Junction Proteins, and ß-Defensins in Filaggrin-Deficient Skin Equivalents.
abstract: Atopic dermatitis is a chronic skin condition with complex etiology. It is characterized by skin barrier defects and T helper type 2 (Th2)-polarized inflammation. Although mutations in the filaggrin gene are known to be prominent genetic risk factors for the development of atopic dermatitis, the interdependency between these and an altered cytokine milieu is not fully understood. In this study, we evaluated the direct effects of filaggrin deficiency on the cornified envelope, tight junction proteins, and innate immune response, and report the effects of Th2 cytokines in normal and filaggrin-deficient skin equivalents. Supplementation with IL-4 and IL-13 led to distinct histologic changes and significantly increased skin surface pH, both of which were enhanced in filaggrin knockdown skin equivalents. We detected a compensatory up-regulation of involucrin and occludin in filaggrin-deficient skin that was dramatically disturbed when simultaneous inflammation occurred. Furthermore, we found that a lack of filaggrin triggered an up-regulation of human ?-defensin 2 via an unknown mechanism, which was abolished by Th2 cytokine supplementation. Taken together, these results indicate that defects in the epidermal barrier, skin permeability, and cutaneous innate immune response are not primarily linked to filaggrin deficiency but are rather secondarily induced by Th2 inflammation.
authors.affiliation: Institute for Pharmaceutical Sciences, Pharmacology & Toxicology, Freie Universität Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hönzke
authors.affiliation: Institute for Pharmaceutical Sciences, Pharmacology & Toxicology, Freie Universität Berlin, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Wallmeyer
authors.affiliation: Department of Veterinary Pathology, Freie Universität Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Ostrowski
authors.affiliation: Department of Veterinary Pathology, Freie Universität Berlin, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Radbruch
authors.affiliation: Department of Veterinary Pathology, Freie Universität Berlin, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Mundhenk
authors.affiliation: Institute for Pharmaceutical Sciences, Pharmacology & Toxicology, Freie Universität Berlin, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
authors.affiliation: Institute for Pharmaceutical Sciences, Pharmacology & Toxicology, Freie Universität Berlin, Germany. Electronic address: sarah.hedtrich@fu-berlin.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hedtrich
mesh_terms: D001707:Biopsy, Needle; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000473:pathology; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D000091344:Filaggrin Proteins; D006801:Humans; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D012016:Reference Values; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D062725:Tight Junction Proteins / Q000378:metabolism*; D023083:beta-Defensins / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D018793:Interleukin-13; D007381:Intermediate Filament Proteins; D062725:Tight Junction Proteins; D023083:beta-Defensins; D015847:Interleukin-4