title: Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide β-endorphin, via STAT3/calcium axis in atopic dermatitis.
abstract: BACKGROUND
  Itch is the cardinal symptom of atopic dermatitis (AD). β-Endorphin, a neuropeptide, is increased in both AD skin and sera. Interleukin (IL)-31, an itch-relevant cytokine, activates IL-31 receptors in keratinocytes. However, how IL-31 and β-endorphin interact in AD skin remains elusive.
  
  
  OBJECTIVE
  To investigate the mechanistic interaction of IL-31 and β-endorphin in AD.
  
  
  METHODS
  This was a prospective cross-sectional study. We recruited adult patients with AD and controls according to Hanifin's AD criteria. Serum levels of IL-31 and β-endorphin were measured by enzyme-linked immunosorbent assay. Expressions of IL-31 receptor A (IL-31RA) and β-endorphin in the skin were assessed by immunohistochemistry. Their expression in the skin and blood was compared and correlated in patients with AD and in controls. We also treated primary keratinocytes with IL-31 and measured calcium influx, β-endorphin production and signalling pathways to define their mechanistic interactions.
  
  
  RESULTS
  β-Endorphin was increased in the supernatant from IL-31-treated keratinocytes. IL-31 receptor activation resulted in calcium influx and STAT3 activation; pretreatment with STAT3 inhibitor stopped the increase of β-endorphin. Notably, either replacement of extracellular calcium or treatment with 2-aminoethoxydiphenyl borate, an inhibitor for the store-operated channel, blocked STAT3 activation. We found higher levels of blood β-endorphin and IL-31, which were significantly correlated, in patients with AD. Moreover, IL-31RA and β-endorphin were increased and colocalized both in AD human skin and TPA-painted mouse skin.
  
  
  CONCLUSIONS
  IL-31 receptor activation in keratinocytes induces calcium influx and STAT3-dependent production of β-endorphin. These results might contribute to an understanding of the regulatory mechanisms underlying peripheral itch.
authors.affiliation: Department of Dermatology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Lee
authors.forename: C-H
authors.initials: CH
authors.lastname: Hong
authors.forename: W-T
authors.initials: WT
authors.lastname: Yu
authors.forename: H-Y
authors.initials: HY
authors.lastname: Chuang
authors.forename: S-K
authors.initials: SK
authors.lastname: Huang
authors.forename: G-S
authors.initials: GS
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Yoshioka
authors.forename: M
authors.initials: M
authors.lastname: Sakata
authors.forename: W-T
authors.initials: WT
authors.lastname: Liao
authors.forename: Y-C
authors.initials: YC
authors.lastname: Ko
authors.forename: H-S
authors.initials: HS
authors.lastname: Yu
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003876:Dermatitis, Atopic / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000097:blood* / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001615:beta-Endorphin / Q000097:blood*
chemical_list: D015415:Biomarkers; C502187:IL31 protein, human; D007378:Interleukins; D050796:STAT3 Transcription Factor; D001615:beta-Endorphin; D002118:Calcium