Sulfasalazine sensitises human monocytic/macrophage cells for glucocorticoids by upregulation of glucocorticoid receptor α and glucocorticoid induced apoptosis
Sulfasalazine sensitises human monocytic/macrophage cells for glucocorticoids by upregulation of glucocorticoid receptor α and glucocorticoid induced apoptosis
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DOI：
10.1136/ard.2006.060509
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发表时间：
2007-10-01
影响因子：
27.4
通讯作者：
Jansen, Gerrit
中科院分区：
文献类型：
--
作者：
Oerlemans, Ruud;Vink, Josefien;Jansen, Gerrit
背景资料：糖皮质激素（GC）通常用于治疗（慢性）炎症性疾病和癌症，但对这些药物的固有或获得性耐药性限制了其最佳疗效。因此，可调节GC抗性的药物的可用性具有潜在的临床意义。目的：探讨GC敏感的GC耐药的单核细胞/巨噬细胞的分子基础后，慢性暴露于sulfasalazin.Methods：人单核细胞/巨噬细胞THP 1和U937细胞代表一个细胞系模型系统，其特征在于固有的抵抗GC地塞米松和泼尼松龙。将两种细胞系在体外长期暴露于0.3-0.6 mM柳氮磺胺吡啶（SSZ）约3个月，之后表征它们的GC敏感性、GC受体和核因子κ B（NF κ B）信号传导途径的组分的表达水平以及它们经历GC诱导的细胞凋亡的能力。长期暴露于SSZ显著使U937和THP 1细胞对地塞米松（分别为781倍和1389倍）和泼尼松龙（分别为562倍和1220倍）敏感。暴露于SSZ的细胞中GC敏感性的恢复是通过GC诱导的细胞凋亡引起的，与NFkB活化的抑制一致。此外，蛋白质印迹分析显示，糖皮质激素受体（GR a）的表达显着增加细胞暴露于SSZ。由于GRa mRNA水平仅略有增加，这些结果表明，改变的转录后机制是可操作的，这赋予了一个稳定的GRa蛋白SSZ exposed cells.Conclusion：这些结果表明，慢性靶向的NF κ B信号通路SSZ可能被利用作为一种新的策略，以稳定GRa的表达，从而敏感的主要耐药细胞GC。
Background: Glucocorticoids (GCs) are commonly used in the treatment of ( chronic) inflammatory diseases and cancer, but inherent or acquired resistance to these drugs limits their optimal efficacy. The availability of drugs that could modulate GC resistance is therefore of potential clinical interest. Objective: To explore the molecular basis of GC sensitisation of GC resistant monocytic/macrophage cells after chronic exposure to sulfasalazine.Methods: Human monocytic/macrophage THP1 and U937 cells represent a cell line model system characterised by inherent resistance to the GCs dexamethasone and prednisolone. Both cell lines were chronically exposed in vitro to 0.3-0.6 mM sulfasalazine (SSZ) for approximately 3 months, after which they were characterised for GC sensitivity, expression levels of GC receptor and components of the nuclear factor kappa B ( NFkB) signalling pathway, and their ability to undergo GC induced apoptosis.Results: Chronic exposure to SSZ markedly sensitised both U937 and THP1 cells to dexamethasone (781-fold and 1389-fold, respectively) and prednisolone (562-fold and 1220-fold, respectively). Restoration of GC sensitivity in cells exposed to SSZ was provoked via GC induced apoptosis, coinciding with inhibition of NFkB activation. Moreover, western blot analysis revealed a markedly increased expression of glucocorticoid receptor a (GRa) in cells exposed to SSZ. Since GRa mRNA levels were only marginally increased, these results suggest that an altered post-transcriptional mechanism was operable which conferred a stable GRa protein on SSZ exposed cells.Conclusion: These results suggest that chronic targeting of the NFkB signalling pathway by SSZ may be exploited as a novel strategy to stabilise GRa expression and thereby sensitise primary resistant cells to GCs.