title: Impact of high-mobility group box 1 on melanocytic survival and its involvement in the pathogenesis of vitiligo.
abstract: BACKGROUND
  Vitiligo is attributable to loss of functional melanocytes and is the most common acquired depigmenting disorder. Oxidative stress and intense ultraviolet irradiation are known to aggravate this condition. The nonhistone high-mobility group box 1 (HMGB1) DNA-binding protein is a physiological activator of immune responses, cellular proliferation and cell death. Although it is implicated in the pathogenesis of autoimmune diseases and cutaneous disorders, the precise role of HMGB1 in melanocytes has yet to be studied.
  
  
  OBJECTIVE
  To elucidate the effect of HMGB1 on melanocytic survival and its involvement in the pathogenesis of vitiligo.
  
  
  METHODS
  Melanocytes were treated with recombinant HMGB1 (rHMGB1). Thereafter, apoptosis-, autophagy- and melanogenesis-related molecules were detected. Ex vivo skin organ culture was performed after rHMGB1 treatment. Also, levels of HMGB1 were examined in blood and skin specimens from patients with vitiligo.
  
  
  RESULTS
  In this study, rHMGB1 increased expression of cleaved caspase 3 and decreased melanin production and expression of melanogenesis-related molecules. rHMGB1-induced caspase 3 activation was confirmed through preincubation with a pan-caspase inhibitor. In ex vivo experiments for the confirmation of HMGB1-induced melanocyte apoptosis, melanocyte disappearance and increased caspase 3 activation were observed in rHMGB1-treated skin tissues. In Western blot analysis and enzyme-linked immunosorbent assay, patients with active vitiligo showed significantly higher blood levels of HMGB1 (vs. healthy controls). Also, greater expression of HMGB1 was observed in vitiliginous skin (vs. uninvolved skin).
  
  
  CONCLUSIONS
  External stimuli (e.g. oxidative stress and ultraviolet irradiation) may trigger HMGB1 release by keratinocytes, thereby perpetuating vitiligo through HMGB1-induced melanocytic apoptosis.
authors: Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors: J Y
authors: JY
authors: Kim
authors: Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors: E J
authors: EJ
authors: Lee
authors: Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors: J
authors: J
authors: Seo
authors: Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors: S H
authors: SH
authors: Oh
mesh_terms: D000328:Adult; D000368:Aged; D001343:Autophagy / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D012867:Skin / Q000378:metabolism; D014466:Ultraviolet Rays; D014820:Vitiligo / Q000209:etiology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; D053148:Caspase 3