title: IL-31 regulates differentiation and filaggrin expression in human organotypic skin models.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Cornelissen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Marquardt
authors.forename: Katharina
authors.initials: K
authors.lastname: Czaja
authors.forename: Jörg
authors.initials: J
authors.lastname: Wenzel
authors.forename: Jorge
authors.initials: J
authors.lastname: Frank
authors.forename: Juliane
authors.initials: J
authors.lastname: Lüscher-Firzlaff
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.forename: Jens M
authors.initials: JM
authors.lastname: Baron
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000378:metabolism*; D000091344:Filaggrin Proteins; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D000099180:Interleukin-24
chemical_list: D000091344:Filaggrin Proteins; D007378:Interleukins; D007381:Intermediate Filament Proteins; D011994:Recombinant Proteins; D000099180:Interleukin-24; C000717249:FLG protein, human; C502187:IL31 protein, human; C422042:interleukin 20