Glucocorticoids mediate differential anti-apoptotic effects in human fibroblasts and keratinocytes via sphingosine-1-phosphate formation
Glucocorticoids mediate differential anti-apoptotic effects in human fibroblasts and keratinocytes via sphingosine-1-phosphate formation
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DOI：
10.1002/jcb.10766
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发表时间：
2004-03-01
影响因子：
4
通讯作者：
Schäfer-Korting, M
中科院分区：
文献类型：
--
作者：
Hammer, S;Sauer, B;Schäfer-Korting, M
糖皮质激素是有效的抗炎和免疫调节药物，也可诱导多种细胞类型的生长抑制。因此，长期治疗炎症性皮肤病可能导致不可逆的皮肤萎缩。为了阐明糖皮质激素在成纤维细胞中的抗增殖作用是否伴随着诱导凋亡，我们研究了地塞米松（DEX）对这两个参数的影响。有趣的是，我们发现，生长抑制浓度的糖皮质激素不会诱导成纤维细胞凋亡。此外，DEX保护这些细胞免于肿瘤坏死因子α（TNF α）/放线菌素，紫外线照射和细胞可渗透的神经酰胺诱导的凋亡。这些发现与在角质形成细胞中检测到的抗凋亡作用的缺乏形成对比。尽管DEX抑制成纤维细胞中TNF α介导的核因子-κ B（NF-κ B）活性，但这种机制并不参与其细胞保护作用，因为特异性NF-κ B抑制剂证实了这一点。因此，我们寻找替代的细胞内介质。成纤维细胞与鞘氨醇激酶抑制剂N，N-二甲基鞘氨醇，它阻止鞘脂降解产物鞘氨醇-1-磷酸（S1 P）的形成共孵育，废除了保护性糖皮质激素的作用几乎完全。由于SIP预孵育减少了TNF α/放线菌素刺激后凋亡细胞的数量，而且DEX增加了细胞内S1 P含量，因此建议这种鞘脂在DEX的细胞保护中起作用。(C)2004 Wiley-Liss，Inc.
Glucocorticoids are potent anti-inflammatory and immunomodulatory drugs which also induce growth inhibition in a variety of cell types. For this reason long-term treatment of inflammatory skin diseases may result in irreversible skin atrophy. To elucidate whether the anti proliferative action of glucocorticoids in fibroblasts is accompanied by induction of apoptosis we investigated the influence of dexamethasone (DEX) on both parameters. Interestingly, we revealed that growth inhibitory concentrations of this glucocorticoid did not induce fibroblast apoptosis. Moreover, DEX protected these cells from apoptosis induced by tumor necrosis factor alpha (TNFalpha)/actinomycin, UV-irradiation, and cell permeable ceramides. These findings are in contrast to the lack of anti-apoptotic effects detected in keratinocytes. Although DEX inhibited TNFalpha mediated nuclear factor-kappa (NF-kappaB) activity in fibroblasts, this mechanism was not involved in its cytoprotection as it was verified by specific NF-kappaB inhibitors. Therefore, we looked for alternative intracellular mediators. Coincubation of fibroblasts with the sphingosine kinase inhibitor N,N-dimethylsphingosine, which blocks formation of the sphingolipid degradation product sphingosine-1-phosphate (S1P), abrogated the protective glucocorticoid effect almost completely. As preincubation with SIP reduced the number of apoptotic cells after stimulation with TNFalpha/actinomycin and moreover DEX increased the intracellular S1P content a role of this sphingolipid in the cytoprotection by DEX is suggested. (C) 2004 Wiley-Liss, Inc.