Lan C-C E, Chen G-S, Chiou M-H, Wu C-S, Chang C-H, Yu H-S
Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Br J Dermatol. 2005 Sep;153(3):498-505. doi: 10.1111/j.1365-2133.2005.06739.x.
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.
To investigate the effects of FK506 on melanocyte (MC) and melanoblast (MB) growth via KCs.
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 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.
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.
白癜风是一种获得性色素脱失性疾病，其特征为皮肤和毛发色素脱失。由于该病的发病机制仍不清楚，白癜风的治疗总体上并不理想，常常令人失望。外用他克莫司（FK506）软膏最近被纳入治疗这种色素脱失性疾病的药物库中。尽管其具有临床疗效，但外用他克莫司在白癜风中诱导色素再生的潜在机制很少被研究。由于他克莫司软膏直接应用于皮肤，其对角质形成细胞（KC）的影响需要深入研究。
研究FK506通过KC对黑素细胞（MC）和黑素母细胞（MB）生长的影响。
用不同浓度的FK506处理KC培养物的上清液，然后用其处理培养的MC和MB。通过观察上清液对MC/MB增殖、黑色素形成和细胞迁移的影响，评估其对MC和MB的作用。评估已知对细胞迁移有影响的基质金属蛋白酶（MMP）-2和MMP-9的活性。还测定了KC上清液中MC/MB生长因子的浓度。
结果表明，FK506处理的KC上清液可显著增强MC和MB的增殖。此外，KC上清液中干细胞因子的浓度随FK506处理呈剂量依赖性增加。FK506处理的KC培养物的上清液显示MMP-9活性显著增加。
我们的研究提供了体外证据，证明FK506与KC之间的直接相互作用为MC的生长和迁移创造了有利环境。此外，我们的研究结果提供了一种可能的机制，解释了他克莫司软膏如何诱导白癜风患者色素再生。
