Journal Article

IL-17 Induces an Expanded Range of Downstream Genes in Reconstituted Human Epidermis Model

Fuentes-Duculan, Judilyn, Guttman-Yassky, Emma, Nograles, Kristine E., Bonifacio, Kathleen M., Suárez-Fariñas, Mayte, Chiricozzi, Andrea, Johnson-Huang, Leanne M., Gulati, Nicholas, Cardinale, Irma, Mitsui, Hiroshi, Krueger, James G.

2014

Overview

IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -β, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes. The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the \"RHE\" genes in psoriasis patients treated in vivo with this IL-17 antagonist.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Autoimmune diseases / Autoimmunity / B cells / beta-Defensins - genetics / beta-Defensins - metabolism / Binding proteins / Biology / CCAAT-Enhancer-Binding Protein-beta - genetics / CCAAT-Enhancer-Binding Protein-beta - metabolism / CCAAT/enhancer-binding protein / Cytokines / Dendritic cells / Dermatitis / Dermatology / Epidermis / Epidermis - cytology / Epidermis - drug effects / Epidermis - metabolism / Gene expression / Gene Expression Profiling / Gene Expression Regulation / Genes / Genomics / Helper cells / Humans / In vitro methods and tests / Inflammation / Interferon / Interleukin 17 / Interleukin-17 - pharmacology / Keratinocytes / Keratinocytes - cytology / Keratinocytes - drug effects / Keratinocytes - metabolism / Laboratories / Lipocalins - genetics / Lipocalins - metabolism / Lymphocytes / Lymphocytes T / Medicine / Monomolecular films / Pathogenesis / Peptides / Probes / Protein binding / Proteins / Psoriasis / Psoriasis vulgaris / Science / Skin / Skin diseases / T cells / Tissue Culture Techniques / Tissue Engineering / Transcription (Genetics) / Tumor necrosis factor / Tumor necrosis factor-TNF / Tumor necrosis factor-α / γ-Interferon