title: TNF-α and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents.
abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disease in which the skin barrier function is disrupted. In this inflammatory AD environment, cytokines are upregulated, but the cytokine effect on the AD skin barrier is not fully understood. We aimed to investigate the influence of Th2 (IL-4, IL-13, IL-31) and pro-inflammatory (tumor necrosis factor alpha (TNF-α)) cytokines on epidermal morphogenesis, proliferation, differentiation, and stratum corneum lipid properties. For this purpose, we used the Leiden epidermal model (LEM) in which the medium was supplemented with these cytokines. Our results show that IL-4, IL-13, IL-31, and TNF-α induce spongiosis, augment TSLP secretion by keratinocytes, and alter early and terminal differentiation-protein expression in LEMs. TNF-α alone or in combination with Th2 cytokines decreases the level of long chain free fatty acids (FFAs) and ester linked ω-hydroxy (EO) ceramides, consequently affecting the lipid organization. IL-31 increases long chain FFAs in LEMs but decreases relative abundance of EO ceramides. These findings clearly show that supplementation with TNF-α and Th2 cytokines influence epidermal morphogenesis and barrier function. As a result, these LEMs show similar characteristics as found in AD skin and can be used as an excellent tool for screening formulations and drugs for the treatment of AD.
authors: Department of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors: Mogbekeloluwa O
authors: MO
authors: Danso
authors: Department of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Vincent
authors: V
authors: van Drongelen
authors: Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Aat
authors: A
authors: Mulder
authors: Department of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors: Jeltje
authors: J
authors: van Esch
authors: Department of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors: Hannah
authors: H
authors: Scott
authors: Department of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors: Jeroen
authors: J
authors: van Smeden
authors: Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Abdoelwaheb
authors: A
authors: El Ghalbzouri
authors: Department of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. Electronic address: bouwstra@lacdr.leidenuniv.nl.
authors: Joke A
authors: JA
authors: Bouwstra
mesh_terms: D001940:Breast / Q000166:cytology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000473:pathology*; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D006801:Humans; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D002518:Ceramides; D016207:Cytokines; D005230:Fatty Acids, Nonesterified; C502187:IL31 protein, human; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D000094632:Thymic Stromal Lymphopoietin