title: Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model.
abstract: BACKGROUND
  Defects in keratinocyte differentiation and skin barrier are important features of inflammatory skin diseases like atopic dermatitis. Mast cells and their main mediator histamine are abundant in inflamed skin and thus may contribute to disease pathogenesis.
  
  
  METHODS
  Human primary keratinocytes were cultured under differentiation-promoting conditions in the presence and absence of histamine, histamine receptor agonists and antagonists. The expression of differentiation-associated genes and epidermal junction proteins was quantified by real-time PCR, Western blot, and immunofluorescence labeling. The barrier function of human skin models was tested by the application of biotin as tracer molecule.
  
  
  RESULTS
  The addition of histamine to human keratinocyte cultures and organotypic skin models reduced the expression of the differentiation-associated proteins keratin 1/10, filaggrin, and loricrin by 80-95%. Moreover, the addition of histamine to skin models resulted in the loss of the granular layer and thinning of the epidermis and stratum corneum by 50%. The histamine receptor H1R agonist, 2-pyridylethylamine, suppressed keratinocyte differentiation to the same extent as did histamine. Correspondingly, cetirizine, an antagonist of H1R, virtually abrogated the effect of histamine. The expression of tight junction proteins zona occludens-1, occludin, claudin-1, and claudin-4, as well as that of desmosomal junction proteins corneodesmosin and desmoglein-1, was down-regulated by histamine. The tracer molecule biotin readily penetrated the tight junction barrier of skin cultures grown in the presence of histamine, while their diffusion was completely blocked in nontreated controls.
  
  
  CONCLUSIONS
  Our findings suggest a new mechanism by which mast cell activation and histamine release contribute to skin barrier defects in inflammatory skin diseases.
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Gschwandtner
authors.forename: M
authors.initials: M
authors.lastname: Mildner
authors.forename: V
authors.initials: V
authors.lastname: Mlitz
authors.forename: F
authors.initials: F
authors.lastname: Gruber
authors.forename: L
authors.initials: L
authors.lastname: Eckhart
authors.forename: T
authors.initials: T
authors.lastname: Werfel
authors.forename: R
authors.initials: R
authors.lastname: Gutzmer
authors.forename: P M
authors.initials: PM
authors.lastname: Elias
authors.forename: E
authors.initials: E
authors.lastname: Tschachler
mesh_terms: D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism*; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D012879:Skin Physiological Phenomena / Q000187:drug effects*; D046509:Tissue Culture Techniques
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D011969:Receptors, Histamine H1; D006632:Histamine