College of Pharmacy, Dongguk University-Seoul, Goyang 410-820, Republic of Korea.
Int J Biochem Cell Biol. 2012 Dec;44(12):2124-8. doi: 10.1016/j.biocel.2012.08.020. Epub 2012 Sep 2.
Vitiligo is a progressive depigmenting disorder. Histamine has been shown to induce melanogenesis via histamine receptor 2, suggesting the possibility of histamine as a repigmenting agent for the treatment of vitiligo. However, the role and signaling mechanism of histamine are still unclear in melanogenesis, especially in relation to growth-differentiation factor-15, which is a protein belonging to transforming growth factor beta and found to be overexpressed in metastatic or malignant melanoma. We found that histamine induces growth-differentiation factor-15 in melanoma cell lines such as SK-MEL-2, B16F10, and melan-a cells. Therefore, in the present study, the role of growth-differentiation factor-15 in histamine-induced melanogenesis was investigated using gene silencing or overexpression of growth-differentiation factor-15 and histamine related compounds such as histamine, amthamine, and cimetidine. Gene silencing of growth-differentiation factor-15 suppressed histamine-induced proliferation, melanin production, tyrosinase activity, and chemotactic migration of SK-MEL-2 cells. Histamine-induced expression of tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2 was also suppressed by growth-differentiation factor-15 gene silencing. On the other hand, overexpression of growth-differentiation factor-15 using a plasmid containing growth-differentiation factor-15 in SK-MEL-2 cells increased melanin production and chemotactic migration. Amthamine induced expression of growth-differentiation factor-15 in a time and concentration dependent manner. Amthamine-induced expression of growth-differentiation factor-15 was suppressed by cimetidine. Our results suggest that growth-differentiation factor-15 is a new player in histamine-induced melanogenesis, which can help researchers to extend the knowledge of the role of the transforming growth factor beta family in melanogenesis and in skin pigment disorders such as vitiligo.
白癜风是一种进行性色素减退疾病。组胺通过组胺受体 2 诱导黑色素生成，这表明组胺有可能成为治疗白癜风的复色剂。然而，组胺在黑色素生成中的作用和信号机制仍不清楚，特别是与生长分化因子 15 有关，生长分化因子 15 是转化生长因子β家族的一种蛋白，在转移性或恶性黑色素瘤中发现过度表达。我们发现组胺可诱导 SK-MEL-2、B16F10 和 melan-a 等黑色素瘤细胞系中生长分化因子 15 的表达。因此，在本研究中，使用生长分化因子 15 的基因沉默或过表达以及组胺相关化合物（如组胺、氨甲酰胆碱和西咪替丁）研究了生长分化因子 15 在组胺诱导的黑色素生成中的作用。生长分化因子 15 的基因沉默抑制了组胺诱导的 SK-MEL-2 细胞增殖、黑色素生成、酪氨酸酶活性和趋化性迁移。生长分化因子 15 的基因沉默也抑制了组胺诱导的酪氨酸酶、酪氨酸酶相关蛋白 1 和酪氨酸酶相关蛋白 2 的表达。另一方面，使用含有生长分化因子 15 的质粒在 SK-MEL-2 细胞中过表达生长分化因子 15 增加了黑色素生成和趋化性迁移。氨甲酰胆碱以时间和浓度依赖的方式诱导生长分化因子 15 的表达。西咪替丁抑制氨甲酰胆碱诱导的生长分化因子 15 的表达。我们的结果表明，生长分化因子 15 是组胺诱导黑色素生成的新成员，这有助于研究人员扩展转化生长因子β家族在黑色素生成以及白癜风等皮肤色素紊乱中的作用的知识。
