title: Keratinocyte-derived anosmin-1, an extracellular glycoprotein encoded by the X-linked Kallmann syndrome gene, is involved in modulation of epidermal nerve density in atopic dermatitis.
abstract: BACKGROUND
  Epidermal nerve density is increased in atopic dermatitis (AD), suggesting that the hyperinnervation is partly responsible for abnormal itch perception. It is probably controlled by axonal guidance molecules produced by keratinocytes. An extracellular matrix glycoprotein anosmin-1 encoded by KAL1 has chemoattractive or chemorepulsive effects on different neuronal types.
  
  
  OBJECTIVE
  This study was performed to investigate the roles of anosmin-1 in skin innervation.
  
  
  METHODS
  Rat dorsal root ganglion (DRG) neurones were cultured in conditioned medium from control or KAL1-overexpressing cells for neurite outgrowth assay. KAL1 expression in cultured epidermal keratinocytes or human skin was examined by quantitative RT-PCR (qRT-PCR). Anosmin-1 distribution in normal and atopic skin was examined immunohistochemically. The effects of calcium concentrations and cytokines on KAL1 expression in cultured normal human epidermal keratinocytes (NHEK) were analysed by qRT-PCR.
  
  
  RESULTS
  Neurite outgrowth in cultured DRG neurones was inhibited by conditioned medium from KAL1-overexpressing cells, while it was rescued by addition of recombinant fibroblast growth factor receptor 1 for capturing anosmin-1. KAL1 transcripts were expressed in cultured keratinocytes or in normal skin. Anosmin-1 was strongly expressed in the basal cell layer of normal skin, but decreased in atopic skin, concomitant with increases of epidermal nerve fibres. KAL1 expression was downregulated during keratinocyte differentiation. The expression was also upregulated by interleukin-4 (IL-4), IL-13 or transforming growth factor (TGF)-beta1. TGF-beta1 acted synergistically with IL-13 to enhance KAL1 expression, while interferon-gamma inhibited its expression.
  
  
  CONCLUSIONS
  Anosmin-1 produced by epidermal keratinocytes in response to calcium concentrations or cytokines may modulate epidermal nerve density in AD.
authors.affiliation: Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, Japan.
authors.forename: Suhandy
authors.initials: S
authors.lastname: Tengara
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Tominaga
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kamo
authors.forename: Kenichi
authors.initials: K
authors.lastname: Taneda
authors.forename: Osamu
authors.initials: O
authors.lastname: Negi
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Takamori
mesh_terms: D000328:Adult; D000818:Animals; D001706:Biopsy; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology; D004817:Epidermis / Q000294:innervation* / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D018793:Interleukin-13; D009419:Nerve Tissue Proteins; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4