Calcineurin activity and inhibition in skin and (epi)dermal cell cultures
Calcineurin activity and inhibition in skin and (epi)dermal cell cultures
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DOI：
10.1038/sj.jid.5701244
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发表时间：
2008-07-01
影响因子：
6.5
通讯作者：
Van Pelt, J.
中科院分区：
文献类型：
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作者：
Smit, N. P. M.;Van Rossum, H. H.;Van Pelt, J.
钙调磷酸酶 (Cn) 是免疫抑制药物环孢素 A (CsA)、他克莫司 (Trl) 和吡美莫司 (Prl) 的靶标。 Trl 和 Prl 经常局部用于治疗各种皮肤病。 Cn抑制剂CsA和Trl主要用于移植患者的维持治疗。然而，长期使用它们会导致皮肤癌风险急剧增加。通过使用新开发的血液中 Cn 测量方法，我们能够证明总皮肤匀浆中的 Cn 活性。与真皮相比，表皮中的活性明显更高。在皮肤细胞培养物中，与角质形成细胞和黑素细胞相比，成纤维细胞显示出最高的活性。在 Cn 抑制剂中，Trl 显示出比 CsA 和 Prl 更强的抑制作用（在成纤维细胞和角质形成细胞培养物中分别为 57% 和 55%）。此外，Trl 的 IC50（半数最大抑制浓度）值最低（在两种不同的成纤维细胞培养物中分别为 0.5 和 1.3 nM）。因此可以在皮肤病样品中研究 Cn 活性及其抑制作用。 Cn 抑制对成纤维细胞和角质形成细胞的影响可能会影响皮肤免疫系统的整体功能。
Calcineurin (Cn) is the target of the immunosuppressive drugs cyclosporine A (CsA), tacrolimus (Trl), and pimecrolimus (Prl). Trl and Prl are often used topically for treatment of various skin diseases. The Cn inhibitors CsA and Trl are mostly used for maintenance therapy of transplant patients. Their long-term use, however, causes a dramatic increase in skin cancer risk. By using a newly developed assay for Cn measurement in blood, we were able to demonstrate Cn activity in total skin homogenates. A significantly higher activity was found in epidermis compared to dermis. In skin cell cultures, fibroblasts showed the highest activity as compared to keratinocytes and melanocytes. Of the Cn inhibitors, Trl showed stronger inhibition than CsA and Prl (57 and 55% in fibroblast and keratinocyte cultures, respectively). Also, the lowest IC50 (the half maximal inhibitory concentration) values were found for Trl (0.5 and 1.3 nM in two different fibroblast cultures). Cn activity and its inhibition can thus be studied in dermatological samples. The effects of Cn inhibition in fibroblasts and keratinocytes may be of influence on the overall functioning of the skin immune system.