Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine production
Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine production
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DOI：
10.1080/19491034.2015.1128610
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发表时间：
2015-11-01
期刊：
影响因子：
3.7
通讯作者：
Eskiw, Christopher H.
中科院分区：
文献类型：
--
作者：
Gillespie, Zoe E.;MacKay, Kimberly;Eskiw, Christopher H.
雷帕霉素是一种众所周知的雷帕霉素靶点（TOR）信号级联的抑制剂;然而，这种药物对正常原代细胞中全局基因组功能和组织的影响知之甚少。为了探索这种影响，我们用雷帕霉素处理原代人包皮成纤维细胞，观察到细胞增殖减少而不引起细胞死亡。在雷帕霉素处理后，染色体18和10被重新定位到类似于通过血清减少诱导成纤维细胞进入静止的位置。虽然发生了类似的变化定位，比较转录组分析表明，雷帕霉素治疗和静止诱导的成纤维细胞之间的基因表达模式显着分歧。雷帕霉素处理诱导细胞因子基因的上调，包括来自白细胞介素（IL）-6信号传导网络的基因，如IL-8和白血病抑制因子（LIF），而静止的成纤维细胞表现出补体和凝血级联相关基因的上调。此外，通过雷帕霉素处理显著上调的基因证明了转录因子信号转导和转录激活因子5A/B（STAT 5A/B）的启动子占用增加。总之，我们证明了用雷帕霉素处理成纤维细胞减少增殖，引起染色体区域重新定位，并诱导STAT 5A/B介导的富含细胞因子的基因表达变化。
Rapamycin is a well-known inhibitor of the Target of Rapamycin (TOR) signaling cascade; however, the impact of this drug on global genome function and organization in normal primary cells is poorly understood. To explore this impact, we treated primary human foreskin fibroblasts with rapamycin and observed a decrease in cell proliferation without causing cell death. Upon rapamycin treatment chromosomes 18 and 10 were repositioned to a location similar to that of fibroblasts induced into quiescence by serum reduction. Although similar changes in positioning occurred, comparative transcriptome analyses demonstrated significant divergence in gene expression patterns between rapamycin-treated and quiescence-induced fibroblasts. Rapamycin treatment induced the upregulation of cytokine genes, including those from the Interleukin (IL)-6 signaling network, such as IL-8 and the Leukemia Inhibitory Factor (LIF), while quiescent fibroblasts demonstrated up-regulation of genes involved in the complement and coagulation cascade. In addition, genes significantly up-regulated by rapamycin treatment demonstrated increased promoter occupancy of the transcription factor Signal Transducer and Activator of Transcription 5A/B (STAT5A/B). In summary, we demonstrated that the treatment of fibroblasts with rapamycin decreased proliferation, caused chromosome territory repositioning and induced STAT5A/B-mediated changes in gene expression enriched for cytokines.