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首页> 外文期刊>American Journal of Physiology >Glutamine inhibits cytokine-induced apoptosis in human colonic epithelial cells via the pyrimidine pathway.
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Glutamine inhibits cytokine-induced apoptosis in human colonic epithelial cells via the pyrimidine pathway.

机译：谷氨酰胺通过嘧啶途径抑制人结肠上皮细胞中细胞因子诱导的凋亡。

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摘要

Glutamine (Gln) prevents apoptosis in intestinal epithelial cells, but the mechanism(s) remain unknown. Gln-derived metabolites include ammonia, glutamate (Glu), glutathione (GSH), and nucleotides. We previously showed that Gln potently inhibited apoptosis in cytokine-treated human colonic HT-29 cells; this effect was specific to Gln, unaffected by Glu, and unrelated to intracellular GSH. The current research examines mechanism(s) for Gln-induced antiapoptotic effects in HT-29 cells treated with TNF-alpha-related apoptosis-inducing ligand (TRAIL). Proliferating cells were treated with Gln or selected Gln metabolites for 24 h. Cells were then treated with TRAIL and Gln or its downstream metabolites, and apoptosis was assessed at 8 h after treatment. The purine and pyrimidine precursors inosine and orotate inhibited TRAIL-induced apoptosis. However, inhibition of purine synthesis with azaserine did not alter the potent antiapoptotic effect of Gln. In contrast, the pyrimidine synthesis inhibitor, acivicin, completely prevented this response. Supplementation with the pyrimidine uracil or the pyrimidine precursor orotate rescued the acivicin-induced blockade of Gln antiapoptotic action. Removal of bicarbonate, a substrate for pyrimidine synthesis, also inhibited the antiapoptotic effects of Gln. Uracil and thymine alone also significantly decreased TRAIL-induced apoptosis. The antiapoptotic effects of Gln were independent of DNA/RNA synthesis as measured by flow cytometry and bromodeoxyuridine incorporation. In conclusion, Gln prevents TRAIL-induced apoptosis in HT-29 cells through a mechanism involving the pyrimidine pathway. Our data also demonstrate the novel antiapoptotic effects of pyrimidine bases and their precursor orotate in these human intestinal cells.
机译：谷氨酰胺（Gln）可以防止肠上皮细胞凋亡，但其机制尚不清楚。 Gln衍生的代谢产物包括氨，谷氨酸（Glu），谷胱甘肽（GSH）和核苷酸。我们先前显示，Gln在细胞因子处理的人结肠HT-29细胞中有效抑制凋亡。这种作用是针对Gln的，不受Glu的影响，与细胞内GSH无关。当前的研究探讨了用TNF-α相关凋亡诱导配体（TRAIL）处理的HT-29细胞中Gln诱导的抗凋亡作用的机制。用Gln或选定的Gln代谢产物处理增殖细胞24小时。然后用TRAIL和Gln或其下游代谢产物处理细胞，并在处理后8小时评估细胞凋亡。嘌呤和嘧啶的前体肌苷和乳清酸盐抑制TRAIL诱导的细胞凋亡。但是，用氮杂嘌呤抑制嘌呤合成不会改变Gln的有效抗凋亡作用。相反，嘧啶合成抑制剂阿西维汀完全阻止了这种反应。补充嘧啶尿嘧啶或嘧啶前体乳清酸盐可以缓解阿西维辛诱导的Gln抗凋亡作用。碳酸氢盐（嘧啶合成的底物）的去除也抑制了Gln的抗凋亡作用。单独的尿嘧啶和胸腺嘧啶也显着降低了TRAIL诱导的细胞凋亡。 Gln的抗凋亡作用与DNA / RNA合成无关，如通过流式细胞术和溴脱氧尿苷掺入所测量。总之，Gln通过涉及嘧啶途径的机制阻止TRAIL诱导的HT-29细胞凋亡。我们的数据还证明了嘧啶碱基及其前体乳清酸盐在这些人肠细胞中的新型抗凋亡作用。

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