Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes
Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes
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DOI：
10.1152/ajpcell.00537.2002
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发表时间：
2003-06-01
影响因子：
5.5
通讯作者：
Kalechman, Y
中科院分区：
文献类型：
--
作者：
Gafter-Gvili, A;Sredni, B;Kalechman, Y
环孢素A （CsA）治疗最常见的副作用之一是多毛。本研究表明，钙调磷酸酶活性与体内毛发角质形成细胞的分化有关，影响这些细胞的活化T细胞核因子（NFAT1）活性。用CsA处理裸鼠或C57BL/6脱毛正常小鼠，可抑制与脱落原相关的角化细胞终末分化标志物的表达，同时抑制钙调磷酸酶和NFAT1核易位。这与裸鼠毛发生长的诱导和正常脱毛小鼠自发脱毛诱导的延迟有关。此外，钙调神经磷酸酶抑制抑制了p21（waf/cip1）和p27（kip1）的表达，而p21和p27通常是由分化诱导的。这也与白细胞介素-1 α表达增加（裸小鼠），转化生长因子- β表达减少（裸小鼠和正常小鼠）以及皮肤中角质细胞生长因子表达没有变化有关。在csa处理的小鼠中，毛囊角质形成细胞中凋亡相关基因产物的表达显著改变。抗凋亡基因Bcl-2与促凋亡基因Bax的表达比例升高，p53表达和白细胞介素-1 β转换酶活性降低。这些数据提供了第一个证据，证明钙调磷酸酶在毛囊角质形成细胞中具有功能活性，并且CsA在体内抑制这些细胞中的钙调磷酸酶- nfat1通路可促进头发生长。
One of the most common side effects of treatment with cyclosporin A (CsA) is hypertrichosis. This study shows that calcineurin activity is associated with hair keratinocyte differentiation in vivo, affecting nuclear factor of activated T cells (NFAT1) activity in these cells. Treatment of nude or C57BL/6 depilated normal mice with CsA inhibited the expression of keratinocyte terminal differentiation markers associated with catagen, along with the inhibition of calcineurin and NFAT1 nuclear translocation. This was associated with induction of hair growth in nude mice and retardation of spontaneous catagen induction in depilated normal mice. Furthermore, calcineurin inhibition blocked the expression of p21(waf/cip1) and p27(kip1), which are usually induced with differentiation. This was also associated with an increase in interleukin-1alpha expression (nude mice), a decrease in transforming growth factor-beta (nude and normal mice), and no change in keratinocyte growth factor expression in the skin. Retardation of catagen in CsA-treated mice was accompanied by significant alterations in apoptosis-related gene product expression in hair follicle keratinocytes. The ratio of the anti-apoptotic Bcl-2 to proapoptotic Bax expression increased, and expression of p53 and interleukin-1beta converting enzyme activity decreased. These data provide the first evidence that calcineurin is functionally active in follicular keratinocytes and that inhibition of the calcineurin-NFAT1 pathway in these cells in vivo by CsA enhances hair growth.