Interleukin-6-type cytokines upregulate expression of multidrug resistance-associated proteins in NHEK and dermal fibroblasts
Interleukin-6-type cytokines upregulate expression of multidrug resistance-associated proteins in NHEK and dermal fibroblasts
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DOI：
10.1111/j.0022-202x.2004.23499.x
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发表时间：
2005-01-01
影响因子：
6.5
通讯作者：
Baron, JM
中科院分区：
文献类型：
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作者：
Dreuw, A;Hermanns, HM;Baron, JM
正常的人表皮角质形成细胞（NHEK）和真皮成纤维细胞表达细胞特异性的外排转运蛋白模式。由于人类皮肤细胞中这些转运蛋白的调控机制尚不清楚，我们分析了炎症细胞因子对多药耐药相关蛋白表达的影响（MRP1, 3,4,5）。通过实时荧光定量PCR、RT-PCR、cDNA芯片、免疫染色和外排实验，我们证明了白介素-6 （IL-6）及其可溶性α受体或肿瘤抑制素M （OSM）刺激NHEK和原代人真皮成纤维细胞24-72小时可导致MRP表达和活性上调。两种细胞因子均诱导信号转导和转录激活因子（STAT）1和STAT3以及丝裂原活化蛋白激酶（MAPK） Erk1/2的强烈激活。OSM还能强烈激活蛋白激酶B。使用MAPK/细胞外信号调节激酶激酶1特异性抑制剂U0126，我们可以排除MAPK对MRP基因表达的刺激作用。然而，对磷脂酰肌醇3-激酶的抑制表明，该途径可能参与了osm介导的真皮成纤维细胞MRP4的上调。几种炎症性皮肤病表现出il -6型细胞因子的表达增强。相应的，在银屑病和扁平苔藓患者的病变皮肤中发现MRP表达上调。
Normal human epidermal keratinocytes (NHEK) and dermal fibroblasts express a cell-specific pattern of efflux transport proteins. Since regulatory mechanisms for these transporters in cells of the human skin were unknown, we analyzed the influence of inflammatory cytokines on the expression of multidrug resistance-associated proteins (MRP1, 3, 4, 5). Using real-time PCR, RT-PCR, cDNA microarray, immunostaining and efflux assays we demonstrated that stimulation of NHEK and primary human dermal fibroblasts with interleukin-6 (IL-6), in combination with its soluble alpha-receptor, or oncostatin M (OSM) for 24-72 h resulted in an upregulation of MRP expression and activity. Both cytokines induced a strong activation of signal transducer and activator of transcription (STAT)1 and STAT3 as well as the mitogen-activated protein kinase (MAPK) Erk1/2. OSM additionally activated proteinkinase B strongly. Using the MAPK/extracellular signal-regulated kinase kinase 1-specific inhibitor U0126 we could exclude a stimulatory effect of MAPK on MRP gene expression. Inhibition of the phosphatidylinositol 3-kinase, however, indicated that this pathway might be involved of OSM-mediated upregulation of MRP4 in dermal fibroblasts. Several inflammatory skin diseases show an enhanced expression of IL-6-type cytokines. Correspondingly, upregulation of MRP expression was found in lesional skin taken from patients with psoriasis and lichen planus.