斯卡多尔诱导肠上皮 Caco-2 细胞炎症反应的分子机制:对结直肠癌和炎症性肠病的影响

IF 5.1 2区 生物学 Q2 CELL BIOLOGY
Cells Pub Date : 2024-10-18 DOI:10.3390/cells13201730
Katsunori Ishii, Kazuma Naito, Dai Tanaka, Yoshihito Koto, Koichi Kurata, Hidehisa Shimizu
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引用次数: 0

摘要

肠上皮细胞中的肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)等炎症细胞因子是炎症性肠病(IBD)和结直肠癌(CRC)的重要诱因。鉴于我们之前的研究发现 TNF-α 在一种色氨酸衍生的肠道微生物群代谢物 Skatole 诱导的肠道上皮 Caco-2 细胞中上调,本研究旨在探讨 Skatole 和 IL-6 与 TNF-α 之间的关系。斯卡图尔提高了IL-6和TNF-α的启动子活性,并增加了IL-6 mRNA的表达和蛋白分泌。除了激活 NF-κB 外,NF-κB 抑制剂 BAY 11-7082 还能降低斯卡托尔诱导的细胞存活率以及 IL-6 和 TNF-α 的 mRNA 表达。细胞外信号调节激酶(ERK)通路抑制剂 U0126 和 p38 抑制剂 SB203580 可抑制 NF-κB 的活化,而 c-Jun N 端激酶(JNK)抑制剂 SP600125 则不能抑制 NF-κB 的活化。U126 和 SB203580 还能降低由斯卡托尔诱导的 IL-6 表达的增加。当CH223191抑制了skatole诱导的AhR活化时,除了促进NF-κB的活化外,IL-6的表达也增强了,其方式与之前报道的TNF-α相似。综上所述,这些结果表明,尽管 AhR 的活化部分抑制了这一过程,但斯卡托尔诱导的 NF-κB 活化可诱导 IL-6 和 TNF-α 的表达。鳐鱼增加 IL-6 和 TNF-α 表达的能力可能会对这些疾病的发生和发展产生重大影响。此外,NF-κB 和 AhR 的活化之间的平衡似乎制约着斯卡托尔诱导的 IL-6 和 TNF-α 表达的增加。因此,本研究结果为色氨酸衍生的肠道微生物群代谢物与结直肠疾病的关联机制提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular Mechanisms of Skatole-Induced Inflammatory Responses in Intestinal Epithelial Caco-2 Cells: Implications for Colorectal Cancer and Inflammatory Bowel Disease.

Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in intestinal epithelial cells significantly contribute to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Given our previous findings that TNF-α is upregulated in intestinal epithelial Caco-2 cells induced by skatole, a tryptophan-derived gut microbiota metabolite, the present study aimed to explore the relationship between skatole and IL-6, alongside TNF-α. Skatole elevated the promoter activity of IL-6 as well as TNF-α, and increased IL-6 mRNA expression and protein secretion. In addition to activating NF-κB, the NF-κB inhibitor BAY 11-7082 reduced skatole-induced cell survival and the mRNA expression of IL-6 and TNF-α. NF-κB activation was attenuated by the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 and the p38 inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. U126 and SB203580 also decreased the skatole-induced increase in IL-6 expression. When skatole-induced AhR activation was inhibited by CH223191, in addition to promoting NF-κB activation, IL-6 expression was enhanced in a manner similar to that previously reported for TNF-α. Taken together, these results suggest that skatole-elicited NF-κB activation induces IL-6 and TNF-α expression, although AhR activation partially suppresses this process. The ability of skatole to increase the expression of IL-6 and TNF-α may significantly affect the development and progression of these diseases. Moreover, the balance between NF-κB and AhR activation appears to govern the skatole-induced increases in IL-6 and TNF-α expression. Therefore, the present findings provide new insights into the mechanisms linking tryptophan-derived gut microbiota metabolites with colorectal disease.

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来源期刊
Cells
Cells Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
9.90
自引率
5.00%
发文量
3472
审稿时长
16 days
期刊介绍: Cells (ISSN 2073-4409) is an international, peer-reviewed open access journal which provides an advanced forum for studies related to cell biology, molecular biology and biophysics. It publishes reviews, research articles, communications and technical notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. Full experimental and/or methodical details must be provided.
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