胆汁盐使食管鳞状细胞对 CD95（Fas/Apo-1 受体）介导的凋亡产生差异敏感性。
Bile salts differentially sensitize esophageal squamous cells to CD95 (Fas/Apo-1 receptor) mediated apoptosis.
机构信息
Department of Surgery, Section of Gastrointestinal Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
出版信息
J Surg Res. 2011 Dec;171(2):504-9. doi: 10.1016/j.jss.2010.05.001. Epub 2010 May 31.
BACKGROUND
The role of nonacidic reflux contents on the pathophysiology of Barrett's esophagus remains poorly understood. We hypothesized that esophageal squamous epithelium differs from Barrett's columnar epithelium in response to bile salts with respect to subsequent changes in the cell surface expression of CD95 (Fas/Apo-1) and sensitivity to CD95-mediated apoptosis.
METHODS
Immortalized esophageal squamous cells (HET-1A) and Barrett's esophagus cells (BAR-T), and esophageal adenocarcinoma cells (Flo-1) were treated with toxic and nontoxic bile salts at concentrations observed in gastroesophageal refluxate. CD95 cell-surface expression and apoptotic response to activating anti-CD95 antibody treatment was determined by FACScan analysis.
RESULTS
Bile salt exposure resulted in a dose-dependent increase in CD95 cell-surface expression in HET-1A cells, but not BAR-T or Flo-1 cells. This response occurred rapidly, within a time-frame inconsistent with de novo protein synthesis and was blocked by protein kinase C (PKC) inhibition. Surprisingly, PKC inhibition in Flo-1 cells resulted in an increase in CD95 cell surface expression. Following bile salt exposure, a corresponding increase in the induction of CD95-mediated apoptosis was observed in HET-1A cells; PKC inhibition sensitized Flo-1 cells to apoptosis.
CONCLUSIONS
Our findings suggest that esophageal squamous cells are sensitized to CD95-mediated apoptosis following bile salt exposure. This differential response, compared with columnar epithelial cells, could exert a selection pressure that contributes to the pathophysiology of Barrett's esophagus.
背景
非酸性反流物在 Barrett 食管的病理生理学中的作用仍知之甚少。我们假设食管鳞状上皮细胞在胆汁盐作用下与 Barrett 柱状上皮细胞不同，表现在细胞表面 CD95（Fas/Apo-1）表达的后续变化以及对 CD95 介导的凋亡的敏感性。
方法
用在胃食管反流物中观察到的浓度处理永生化食管鳞状细胞（HET-1A）和 Barrett 食管细胞（BAR-T）以及食管腺癌细胞（Flo-1）。通过 FACScan 分析确定 CD95 细胞表面表达和对激活的抗 CD95 抗体治疗的凋亡反应。
结果
胆汁盐暴露导致 HET-1A 细胞中 CD95 细胞表面表达呈剂量依赖性增加，但 BAR-T 或 Flo-1 细胞则不然。这种反应发生得很快，与新蛋白合成的时间框架不一致，并且被蛋白激酶 C（PKC）抑制所阻断。令人惊讶的是，PKC 抑制在 Flo-1 细胞中导致 CD95 细胞表面表达增加。在胆汁盐暴露后，在 HET-1A 细胞中观察到 CD95 介导的凋亡诱导相应增加；PKC 抑制使 Flo-1 细胞对凋亡敏感。
结论
我们的发现表明，食管鳞状细胞在胆汁盐暴露后易发生 CD95 介导的凋亡。与柱状上皮细胞相比，这种差异反应可能对 Barrett 食管的病理生理学产生选择压力。
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