title: Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin.
abstract: BACKGROUND
  Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a disturbed epidermal barrier. In a subset of patients, this is explained by nonsense mutations in the gene encoding filaggrin (FLG).
  
  
  OBJECTIVE
  We sought to evaluate the respective role of FLG mutations and proinflammatory cytokines and to assess the expression of FLG, hornerin (HRNR), and FLG2, 2 FLG-like proteins, which are involved in epidermal barrier functions, in normal skin and both lesional and nonlesional skin of patients with AD.
  
  
  METHODS
  An FLG-genotyped cohort of 73 adults with AD and 73 aged-matched control subjects was analyzed by using immunohistochemistry and immunoblotting. Normal primary human keratinocytes were differentiated in either the absence or presence of IL-4, IL-13, and IL-25.
  
  
  RESULTS
  Compared with control subjects, FLG, HRNR, and FLG2 were detected at significantly lower levels in the skin of patients with AD, irrespective of their FLG genotype. The reduction was greater in lesional compared with nonlesional skin. In addition, the proFLG/FLG ratio was found to be higher in the skin of wild-type patients than in control subjects. Cytokine treatment of keratinocytes induced a dramatic reduction in FLG, FLG2, and HRNR expression both at the mRNA and protein levels.
  
  
  CONCLUSIONS
  The stratum corneum of lesional but also clinically unaffected skin of adults with AD is abnormal, with reduced expression of FLG and FLG-like proteins. In addition to nonsense mutations, proinflammatory cytokines and some defects in the proFLG processing can contribute to the FLG downregulation. Our study suggests that skin inflammation reduces the expression of FLG-like proteins, contributing to the AD-related epidermal barrier dysfunction.
authors: UMR5165 CNRS, U1056 INSERM, University of Toulouse, Department of Dermatology, University Hospital of Toulouse, Toulouse, France.
authors: Laurence
authors: L
authors: Pellerin
authors: Julie
authors: J
authors: Henry
authors: Chiung-Yueh
authors: CY
authors: Hsu
authors: Stéfana
authors: S
authors: Balica
authors: Catherine
authors: C
authors: Jean-Decoster
authors: Marie-Claire
authors: MC
authors: Méchin
authors: Britta
authors: B
authors: Hansmann
authors: Elke
authors: E
authors: Rodriguez
authors: Stefan
authors: S
authors: Weindinger
authors: Anne-Marie
authors: AM
authors: Schmitt
authors: Guy
authors: G
authors: Serre
authors: Carle
authors: C
authors: Paul
authors: Michel
authors: M
authors: Simon
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D000091344:Filaggrin Proteins; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000235:genetics* / Q000276:immunology; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D061251:Primary Cell Culture; D009418:S100 Proteins / Q000235:genetics* / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000473:pathology
chemical_list: D002135:Calcium-Binding Proteins; C000717249:FLG protein, human; C000717250:FLG2 protein, human; D000091344:Filaggrin Proteins; C503908:HRNR protein, human; C578095:IL13 protein, human; C486701:IL25 protein, human; C508598:IL4 protein, human; D018793:Interleukin-13; D020381:Interleukin-17; D007381:Intermediate Filament Proteins; D009418:S100 Proteins; D015847:Interleukin-4