Delineation of an antiapoptotic action of glucocorticoids in hepatoma cells:: The role of nuclear factor-κB
Delineation of an antiapoptotic action of glucocorticoids in hepatoma cells:: The role of nuclear factor-κB
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DOI：
10.1210/en.141.5.1854
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发表时间：
2000-05-01
期刊：
影响因子：
4.8
通讯作者：
Cidlowski, JA
中科院分区：
文献类型：
--
作者：
Evans-Storms, RB;Cidlowski, JA
糖皮质激素主要因其深刻的抗炎作用和诱导淋巴细胞凋亡的能力而被认可。我们在这里报道，与糖皮质激素对免疫系统细胞的作用相反，糖皮质激素抑制血清剥夺诱导的大鼠肝癌（HTC）细胞凋亡。这些细胞的凋亡抑制发生在糖皮质激素的生理浓度下，并被糖皮质激素拮抗剂RU486所消除。尽管HTC细胞也表达黄体酮、雌激素和甲状腺激素的受体，但这些受体的配体不能使这些细胞免于程序性细胞死亡。由于细胞对凋亡刺激的敏感性通常由抗凋亡与促凋亡的Bcl-2家族成员的比例调节，我们分析了糖皮质激素和血清饥饿诱导凋亡对这些蛋白表达的影响。两种治疗均未改变Bcl-2、Bcl-x(L)、Bad、Bak和Bar水平。线粒体功能最近被认为是包括肝细胞在内的许多细胞凋亡的关键早期调节因子。在血清剥夺诱导HTC细胞凋亡期间，地塞米松治疗阻断了该电位（δ psi(m)）的下降，表明该激素在线粒体上游的作用。我们还发现，HTC细胞凋亡的诱导与核因子(NF)-kappa B的减少有关，地塞米松治疗有效地阻断了核NF-kappa B的丢失，表明该激素通过调节该核转录因子抑制HTC细胞凋亡。转染实验证实了这一假设，表明nf - κ B超抑制因子的表达抑制地塞米松对血清剥夺诱导的HTC细胞凋亡的拯救能力。
Glucocorticoids are primarily recognized for their profound antiinflammatory actions and their ability to induce lymphocyte apoptosis. We report here that, in contrast to their effect on cells of the immune system, glucocorticoids suppress serum deprivation induced apoptosis of rat hepatoma (HTC) cells. Suppression of apoptosis in these cells occurs at physiological concentrations of glucocorticoid and is abrogated by the glucocorticoid antagonist RU486. Although HTC cells also express receptors for progesterone, estrogen, and thyroid hormone, ligands for these receptors fail to rescue these cells from programmed cell death. Because the sensitivity of cells to apoptotic stimuli is often regulated by the ratio of antiapoptotic to proapoptotic Bcl-2 family members, we analyzed the influence of glucocorticoids and induction of apoptosis by serum starvation on the expression of these proteins. Bcl-2, Bcl-x(L), Bad, Bak, and Bar levels were not altered by either treatment. Mitochondrial function has recently been implicated as a critical early regulator of apoptosis in many cells including hepatocytes. Dexamethasone treatment blocked a decrease in this potential (Delta psi(m)) during serum deprivation induced apoptosis in HTC cells, indicating an action of this hormone upstream of mitochondria. We also show that the induction of apoptosis in HTC cells is associated with a decrease in nuclear factor (NF)-kappa B. Treatment with dexamethasone effectively blocked the loss of nuclear NF-kappa B, suggesting that this hormone acts to suppress apoptosis of HTC cells via regulation of this nuclear transcription factor. This hypothesis was confirmed by transfection experiments that show that expression of a superrepressor of NF-kappa B inhibits the ability of dexamethasone to rescue HTC cells from apoptosis induced by serum deprivation.