JAK1/3 inhibition preserves epidermal morphology in full-thickness 3D skin models of atopic dermatitis and psoriasis.

Autor: Clarysse K; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Brussels, Belgium., Pfaff CM; Department of Dermatology and Allergology, Medical School, RWTH Aachen University, Aachen, Germany.; Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany., Marquardt Y; Department of Dermatology and Allergology, Medical School, RWTH Aachen University, Aachen, Germany., Huth L; Department of Dermatology and Allergology, Medical School, RWTH Aachen University, Aachen, Germany., Kortekaas Krohn I; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Brussels, Belgium., Kluwig D; Department of Dermatology and Allergology, Medical School, RWTH Aachen University, Aachen, Germany., Lüscher B; Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany., Gutermuth J; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Brussels, Belgium., Baron J; Department of Dermatology and Allergology, Medical School, RWTH Aachen University, Aachen, Germany.
Jazyk: angličtina
Zdroj: Journal of the European Academy of Dermatology and Venereology : JEADV [J Eur Acad Dermatol Venereol] 2019 Feb; Vol. 33 (2), pp. 367-375. Date of Electronic Publication: 2019 Jan 01.
DOI: 10.1111/jdv.15301
Abstrakt: Background: Janus kinase (JAK) inhibition may be a promising new treatment modality for inflammatory (skin) diseases. However, little is known about direct effects of kinase inhibitors on keratinocyte differentiation and function as well as skin barrier formation.
Objective: Our aim was to address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on keratinocyte immune function and barrier formation in atopic dermatitis (AD) and psoriasis.
Methods: 3D skin equivalents of both diseases were developed and concurrently pretreated with tofacitinib. To induce AD, 3D skin equivalents were stimulated with recombinant human IL-4 and IL-13. Psoriasis-like conditions were induced by incubation with IL-17A, IL-22 and tumour necrosis factor α (TNFα). The activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT6 was assessed by Western blot analysis. Microarray analysis and quantitative real-time PCR were used for gene expression analysis.
Results: Tofacitinib pretreatment preserved epidermal morphology and reduced STAT3 and STAT6 phosphorylation of AD-like and STAT3 phosphorylation of psoriasis-like culture conditions in 3D skin models compared to sham-controls. Filaggrin expression was fully maintained in the AD-like models, but only partially in psoriasis-like conditions after pretreatment with tofacitinib. In addition, tofacitinib upregulated DSC1, FLG and KRT1. Using gene expression analysis, downregulation of POSTN and IL24 was observed in AD-like conditions, whereas downregulation of IL20 and IL1B was observed in psoriasis-like conditions.
Conclusion: JAK1/3 inhibition counteracted cytokine-induced AD- and psoriasis-like epidermal morphology and enhanced keratinocyte differentiation in 3D skin models. This effect was more pronounced in the AD-like models compared to the psoriasis-like 3D skin models.
(© 2018 European Academy of Dermatology and Venereology.)
Databáze: MEDLINE
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