Involvement of the ABC-transporter ABCC1 and the sphingosine 1-phosphate receptor subtype S1P3 in the cytoprotection of human fibroblasts by the glucocorticoid dexamethasone
Involvement of the ABC-transporter ABCC1 and the sphingosine 1-phosphate receptor subtype S1P3 in the cytoprotection of human fibroblasts by the glucocorticoid dexamethasone
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DOI：
10.1007/s00109-009-0468-x
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发表时间：
2009-06-01
影响因子：
4.7
通讯作者：
Kleuser, Burkhard
中科院分区：
文献类型：
--
作者：
Nieuwenhuis, Barbara;Lueth, Anja;Kleuser, Burkhard
糖皮质激素（GC）是治疗急性和慢性炎症性皮肤病最常用的药物。然而，GC的局部长期治疗受到皮肤萎缩发生的限制。最有趣的是，虽然GC抑制人成纤维细胞的增殖，但它们发挥明显的抗过敏作用。在本研究中，我们进一步阐明了GC地塞米松（Dex）保护人成纤维细胞免于程序性细胞死亡的分子机制。地塞米松不仅显著改变了胞质同工酶鞘氨醇激酶1的表达，而且还启动了鞘脂鞘氨醇1-磷酸（S1 P）的增强的细胞内形成。使用S1 P（3）（（-/-））-成纤维细胞的研究表明，该S1 P受体亚型对于Dex诱导的细胞保护是必需的。此外，我们证明ATP结合盒（ABC）转运蛋白ABCC 1被Dex上调，可能是将S1 P从胞质转运到S1 P（3）受体亚型的关键载体。
Glucocorticoids (GC) represent the most commonly used drugs for the treatment of acute and chronic inflammatory skin diseases. However, the topical long-term therapy of GC is limited by the occurrence of skin atrophy. Most interestingly, although GC inhibit proliferation of human fibroblasts, they exert a pronounced anti-apoptopic action. In the present study, we further elucidated the molecular mechanism of the GC dexamethasone (Dex) to protect human fibroblasts from programmed cell death. Dex not only significantly alters the expression of the cytosolic isoenzyme sphingosine kinase 1 but also initiated an enhanced intracellular formation of the sphingolipid sphingosine 1-phosphate (S1P). Investigations using S1P (3) ((-/-)) -fibroblasts revealed that this S1P-receptor subtype is essential for the Dex-induced cytoprotection. Moreover, we demonstrate that the ATP-binding cassette (ABC)-transporter ABCC1 is upregulated by Dex and may represent a crucial carrier to transport S1P from the cytosol to the S1P(3)-receptor subtype.