Ca2+- and PKC-dependent stimulation of PGE2 synthesis by deoxycholic acid in human colonic fibroblasts.
Ca2+- and PKC-dependent stimulation of PGE2 synthesis by deoxycholic acid in human colonic fibroblasts.
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DOI：
10.1152/ajpgi.00525.2001
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发表时间：
2002-09
期刊：
影响因子：
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通讯作者：
Yingting Zhu;P. Hua;Shazia Rafiq;Eric J Waffner;M. Duffey;P. Lance
中科院分区：
文献类型：
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作者：
Yingting Zhu;P. Hua;Shazia Rafiq;Eric J Waffner;M. Duffey;P. Lance
我们研究了前列腺素类生物合成的人结肠成纤维细胞（CCD-18 Co细胞和9个原代成纤维细胞培养物）暴露于初级（胆酸，CA）或二级（脱氧胆酸，DCA）胆汁酸。CCD-18 Co培养物和正常结肠和腺癌结肠的成纤维细胞株的基础PGE 2水平分别为1.7 +/- 0.3、4.0 +/- 2.0和15.0 +/- 4.8 ng/mg蛋白。暴露于DCA（300 μ M）后24小时的峰值水平分别上升了7倍，6倍和7倍，但CA没有引起这样的反应。前列腺素E2合成增加之前，连续增加PGH合酶-2 mRNA和蛋白质表达，并完全防止了非选择性（吲哚美辛）或选择性（塞来昔布）非甾体抗炎药。DCA，而不是CA，引起突然，短暂增加成纤维细胞内钙离子浓度（[Ca 2 +]i）约1分钟后曝光。增加[Ca 2 +]i是DCA介导的PGE 2合成诱导所必需的，蛋白激酶C是该信号通路的另一个重要组成部分。结肠成纤维细胞可能是由粪便胆汁酸诱导的前列腺素类生物合成的主要靶点，并且可能是这些药物的其他有害作用。
We investigated prostanoid biogenesis by human colonic fibroblasts (CCD-18Co cells and nine primary fibroblast cultures) exposed to a primary (cholic, CA) or a secondary (deoxycholic, DCA) bile acid. Basal PGE2 levels in CCD-18Co cultures and fibroblast strains initiated from normal and adenocarcinomatous colon, respectively, were 1.7 +/- 0.3, 4.0 +/- 2.0, and 15.0 +/- 4.8 ng/mg protein. Peak levels 24 h after exposure to DCA (300 microM) rose, respectively, seven-, six- and sevenfold, but CA elicited no such responses. Increases in PGE2 synthesis were preceded by sequential increases in PGH synthase-2 mRNA and protein expression and were fully prevented by a nonselective (indomethacin) or a selective (celecoxib) nonsteroidal anti-inflammatory drug. DCA, but not CA, caused abrupt, transient increases in fibroblast intracellular Ca2+ concentration ([Ca2+]i) approximately 1 min after exposure. Increased [Ca2+]i was required for DCA-mediated induction of PGE2 synthesis, and protein kinase C was a further essential component of this signaling pathway. Colonic fibroblasts may be a major target for prostanoid biogenesis induced by fecal bile acids and, potentially, other noxious actions of these agents.