title: Th2 cytokines enhance TrkA expression, upregulate proliferation, and downregulate differentiation of keratinocytes.
abstract: BACKGROUND
  Nerve growth factor (NGF), a neurotrophin that plays a critical role in developmental neurobiology, is released by proliferating keratinocytes and induces proliferation.
  
  
  OBJECTIVE
  The aim of this study was to investigate the role of tyrosine kinase receptor A (TrkA), a high-affinity receptor of NGF, in human keratinocytes.
  
  
  METHODS
  Expression of TrkA and NGF in skin diseases was investigated by immunohistochemistry. Expression of TrkA in cells was examined by Western blotting and RT-PCR. Cell proliferation was assessed by BrdU assay.
  
  
  RESULTS
  We first determined the expression of TrkA and NGF in skin samples from patients with atopic dermatitis, prurigo nodularis, psoriasis vulgaris, and seborrheic keratosis. TrkA was only expressed in proliferating basal cells, and its expression was enhanced in atopic dermatitis samples. NGF expression was enhanced in atopic dermatitis and prurigo nodularis samples and in some samples from seborrheic keratosis patients. Investigation of the role of TrkA in vitro using normal human epidermal keratinocytes (NHEK) revealed that TrkA was significantly enhanced by the T helper type 2 (Th2) cytokines interleukin (IL)-4 and IL-13 but not by other inflammatory cytokines, such as IL-1β, tumor necrosis factor α, interferon γ, or epidermal growth factor. On the other hand, expression of NGF was not altered by Th2 cytokines. Notably, inhibition of TrkA significantly reversed the effects of IL-4 on proliferation and differentiation. Furthermore, overexpression of TrkA enhanced proliferation of NHEK. These results indicate that IL-4-induced TrkA expression in keratinocytes modulates proliferation and differentiation of these cells.
  
  
  CONCLUSIONS
  Increased TrkA expression in keratinocytes in atopic dermatitis may contribute to the observed epidermal hyperproliferation in these patients.
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Osaka, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Osaka, Japan. Electronic address: mterao@derma.med.osaka-u.ac.jp.
authors.forename: Mika
authors.initials: M
authors.lastname: Terao
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Murota
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Osaka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D020932:Nerve Growth Factor / Q000032:analysis; D020917:Receptor, trkA / Q000032:analysis / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D018793:Interleukin-13; C502240:NGF protein, human; D015847:Interleukin-4; D020932:Nerve Growth Factor; D020917:Receptor, trkA
keywords: Differentiation; IL-4; Keratinocytes; Nerve growth factor; Proliferation; Tyrosine kinase receptor A