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IL-31 regulates differentiation and filaggrin expression in human organotypic skin models

Published:December 19, 2011DOI:https://doi.org/10.1016/j.jaci.2011.10.042

      Background

      Atopic dermatitis (AD) is an inflammatory skin disease affecting 10% to 20% of children and 1% to 3% of adults in industrialized countries. Enhanced expression of IL-31 is detected in skin samples of patients with AD, but its physiological relevance is not known.

      Objective

      We sought to determine the role of IL-31 in skin differentiation.

      Methods

      We used human 3-dimensional organotypic skin models with either primary keratinocytes or HaCaT keratinocytes with inducible IL-31 receptor α to evaluate the effect of IL-31. The consequences were studied by using histology, the expression of markers analyzed by immunofluoresence and quantitative RT-PCR, and gene expression arrays.

      Results

      We observed that IL-31 interferes with keratinocyte differentiation. Gene expression analysis revealed a limited set of genes deregulated in response to IL-31, including IL20 and IL24. In HaCaT keratinocytes with inducible IL-31 receptor α, IL-31 inhibited proliferation upon induction of IL-31 receptor α by inducing cell cycle arrest. As in primary cells, IL-31–treated HaCaT cells elicited a differentiation defect in organotypic skin models, associated with reduced epidermal thickness, disturbed epidermal constitution, altered alignment of the stratum basale, and poor development of the stratum granulosum. The differentiation defect was associated with a profound repression of terminal differentiation markers, including filaggrin, an essential factor for skin barrier formation, and a reduced lipid envelope. The highly induced proinflammatory cytokines IL-20 and IL-24 were responsible for part of the effect on FLG expression and thus for terminal differentiation.

      Conclusion

      Our study suggests that IL-31 is an important regulator of keratinocyte differentiation and demonstrates a link between the presence of IL-31 in skin, as found in patients with AD, and filaggrin expression.

      Key words

      Abbreviations used:

      3D (Three-dimensional), AD (Atopic dermatitis), IL-31RA (IL-31 receptor α), JAK (Janus kinase), MCs (Mast cells), NHEKs (Normal human epidermal keratinocytes), OSMRβ (Oncostatin M receptor β), PI3K (Phosphoinositide-3-kinase), STAT (Signal transducer and activator of transcription)
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