title: FK506 promotes melanocyte and melanoblast growth and creates a favourable milieu for cell migration via keratinocytes: possible mechanisms of how tacrolimus ointment induces repigmentation in patients with vitiligo.
abstract: BACKGROUND
  Vitiligo is an acquired pigmentary disorder characterized by depigmentation of skin and hair. As the pathogenesis of this disease is still obscure, the treatment of vitiligo has generally been unsatisfactory and often disappointing. Topical tacrolimus (FK506) ointment has recently been added to the armamentarium against this pigmentary disorder. Despite its clinical efficacy, the underlying mechanisms of how topical tacrolimus induces repigmentation in vitiligo have rarely been investigated. As tacrolimus ointment is applied directly to the skin, its impact on keratinocytes (KCs) requires thorough investigation.
  
  
  OBJECTIVE
  To investigate the effects of FK506 on melanocyte (MC) and melanoblast (MB) growth via KCs.
  
  
  METHODS
  Cultured MCs and MBs were treated with supernatant of KC cultures conditioned with various concentrations of FK506. The impact of supernatant on MCs and MBs was assessed in terms of its effect on MC/MB proliferation, melanin formation and cell migration. The activities of matrix metalloproteinase (MMP)-2 and MMP-9, known for their influence on cell migration, were evaluated. The concentrations of MC/MB growth factors in the KC supernatant were also determined.
  
  
  RESULTS
  Results demonstrated that proliferation of both MCs and MBs was significantly enhanced by FK506-treated KC supernatant. In addition, the concentration of stem cell factor in KC supernatant increased dose-dependently with FK506 treatment. The supernatant from FK506-treated KC culture showed a significant increase in MMP-9 activity.
  
  
  CONCLUSIONS
  Our study provides in vitro evidence demonstrating that direct interaction between FK506 and KCs creates a favourable milieu for MC growth and migration. Furthermore, our findings provide a possible mechanism explaining how tacrolimus ointment induces repigmentation in patients with vitiligo.
authors.affiliation: Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: C-C E
authors.initials: CC
authors.lastname: Lan
authors.forename: G-S
authors.initials: GS
authors.lastname: Chen
authors.forename: M-H
authors.initials: MH
authors.lastname: Chiou
authors.forename: C-S
authors.initials: CS
authors.lastname: Wu
authors.forename: C-H
authors.initials: CH
authors.lastname: Chang
authors.forename: H-S
authors.initials: HS
authors.lastname: Yu
mesh_terms: D000328:Adult; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004305:Dose-Response Relationship, Drug; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009824:Ointments; D019089:Stem Cell Factor / Q000494:pharmacology; D013268:Stimulation, Chemical; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use; D014820:Vitiligo / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D017077:Culture Media, Conditioned; D006133:Growth Substances; D007166:Immunosuppressive Agents; D008543:Melanins; D009824:Ointments; D019089:Stem Cell Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D016559:Tacrolimus