Department of Dermatology, College of Medicine, Dong-A University, Busan, Korea.
J Eur Acad Dermatol Venereol. 2013 May;27(5):609-16. doi: 10.1111/j.1468-3083.2012.04498.x. Epub 2012 Mar 9.
Vitiligo is an acquired pigmentary disorder caused by the destruction of melanocytes. Two of the major theories regarding the pathogenesis of vitiligo are the autoimmune theory and autocytotoxicity theory, but, the precise pathogenetic mechanism is still not clarified.
We investigated the effects of ET-1, tacrolimus and tumour necrosis factor-α (TNF-α) on proliferation and migration of cultured normal human melanocytes (NHMs). We also sought to clarify the theoretical rationale underlying the topical tacrolimus monotherapy or tacrolimus-UV combination therapy as tools for vitiligo treatment.
The effects of ET-1, tacrolimus and TNF-α on proliferation/migration of cultured NHMs were investigated by MTT assay/Boyden chamber transwell migration assay. We also examined roles of CXC-chemokine receptor II (CXCR II) and matrix metalloproteinases (MMPs) in such conditions.
ET-1 exerted a stimulatory effect on melanocyte proliferation and migration, but, tacrolimus exerted a stimulatory effect only on melanocyte migration higher than ET-1. TNF-α inhibited melanocyte proliferation in a dose-dependent manner. Paradoxically, TNF-α-pretreated NHMs exhibited an enhanced proliferative efficiency after being switched to ET-1. We found CXCRII was highly expressed in TNF-α-incubated melanocytes than the agents-free control, and ET-1 treatment after TNF-α preincubation showed the higher levels of CXCRII expression than the condition incubated with TNF-α alone. Moreover, the greater activities of MMP-2 and MMP-9 induced by tacrolimus than ET-1, reflected tacrolimus would enhance migration stimulatory effect in cultured NHMs.
Topical tacrolimus can be used an effective agent for vitiligo treatment as monotherapy, maybe due to its migration stimulatory action or TNF-α inhibitory property, and also as a component in combination therapy with UV treatment, considering the more upregulated MMPs activities are induced and the more effective migrations are feasible by itself than ET-1.
白癜风是一种由黑素细胞破坏引起的获得性色素障碍性疾病。关于白癜风发病机制的两个主要理论是自身免疫理论和自身细胞毒性理论，但确切的发病机制仍未阐明。
我们研究了内皮素-1（ET-1）、他克莫司和肿瘤坏死因子-α（TNF-α）对培养的正常人黑素细胞（NHM）增殖和迁移的影响。我们还试图阐明他克莫司局部治疗或他克莫司-UV 联合治疗作为白癜风治疗工具的理论依据。
通过 MTT 分析/ Boyden 室透膜迁移分析研究 ET-1、他克莫司和 TNF-α对培养的 NHM 增殖/迁移的影响。我们还研究了 CXC-趋化因子受体 II（CXCR II）和基质金属蛋白酶（MMPs）在这些条件下的作用。
ET-1 对黑素细胞增殖和迁移有刺激作用，但他克莫司对黑素细胞迁移的刺激作用高于 ET-1。TNF-α 呈剂量依赖性抑制黑素细胞增殖。矛盾的是，TNF-α 预处理的 NHM 在切换到 ET-1 后表现出更高的增殖效率。我们发现 CXCRII 在 TNF-α 孵育的黑素细胞中表达水平高于无药物对照，且 ET-1 处理 TNF-α 预处理的 NHM 后，CXCRII 的表达水平高于单独孵育 TNF-α 的条件。此外，他克莫司诱导的 MMP-2 和 MMP-9 的活性高于 ET-1，这反映了他克莫司在培养的 NHM 中增强了迁移刺激作用。
局部他克莫司可作为单一疗法有效治疗白癜风，可能是由于其迁移刺激作用或 TNF-α 抑制作用，也可作为与 UV 治疗联合治疗的组成部分，考虑到诱导的 MMPs 活性更高，并且自身比 ET-1 更有效地迁移。
