Ursolic Acid Inhibits Na+/K+-ATPase Activity and Prevents TNF-α-Induced Gene Expression by Blocking Amino Acid Transport and Cellular Protein Synthesis.
Ursolic Acid Inhibits Na+/K+-ATPase Activity and Prevents TNF-α-Induced Gene Expression by Blocking Amino Acid Transport and Cellular Protein Synthesis.
复制标题
DOI：
10.3390/biom1010032
复制
发表时间：
2011-11-07
期刊：
影响因子：
5.5
通讯作者：
Kataoka T
中科院分区：
文献类型：
--
作者：
Yokomichi T;Morimoto K;Oshima N;Yamada Y;Fu L;Taketani S;Ando M;Kataoka T
促炎细胞因子，如肿瘤坏死因子(TNF)-α，可诱导多种基因的表达，包括细胞间粘附分子-1 （ICAM-1）。熊果酸（3β-羟基-熊胆-12-烯-28-酸）可抑制促炎因子诱导的人肺癌A549细胞表面ICAM-1的表达。熊果酸几乎完全抑制TNF-α-诱导的ICAM-1蛋白表达，而熊果酸仅部分抑制TNF-α-诱导的ICAM-1 mRNA表达和NF-κB信号通路。与这些发现一致，熊果酸阻止细胞蛋白质合成和氨基酸摄取，但对核苷摄取和随后的DNA/RNA合成没有明显影响。熊果酸的这种抑制特征与Na+/K+- atp酶抑制剂瓦巴因相似，但与翻译抑制剂环己亚胺不同。熊果酸对Na+/K+- atp酶的催化活性有抑制作用。因此，本研究揭示了熊果酸抑制Na+/K+- atp酶活性并通过阻断氨基酸转运和细胞蛋白合成来阻止TNF-α-诱导的基因表达的一种新的分子机制。
Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, induce the expression of a wide variety of genes, including intercellular adhesion molecule-1 (ICAM-1). Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) was identified to inhibit the cell-surface ICAM-1 expression induced by pro-inflammatory cytokines in human lung carcinoma A549 cells. Ursolic acid was found to inhibit the TNF-α-induced ICAM-1 protein expression almost completely, whereas the TNF-α-induced ICAM-1 mRNA expression and NF-κB signaling pathway were decreased only partially by ursolic acid. In line with these findings, ursolic acid prevented cellular protein synthesis as well as amino acid uptake, but did not obviously affect nucleoside uptake and the subsequent DNA/RNA syntheses. This inhibitory profile of ursolic acid was similar to that of the Na+/K+-ATPase inhibitor, ouabain, but not the translation inhibitor, cycloheximide. Consistent with this notion, ursolic acid was found to inhibit the catalytic activity of Na+/K+-ATPase. Thus, our present study reveals a novel molecular mechanism in which ursolic acid inhibits Na+/K+-ATPase activity and prevents the TNF-α-induced gene expression by blocking amino acid transport and cellular protein synthesis.