Probiotic Lactobacillus reuteri promotes TNF-induced apoptosis in human myeloid leukemia-derived cells by modulation of NF-κB and MAPK signalling
Probiotic Lactobacillus reuteri promotes TNF-induced apoptosis in human myeloid leukemia-derived cells by modulation of NF-κB and MAPK signalling
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DOI：
10.1111/j.1462-5822.2008.01137.x
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发表时间：
2008-07-01
影响因子：
3.4
通讯作者：
Versalovic, James
中科院分区：
文献类型：
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作者：
Iyer, Chandra;Kosters, Astrid;Versalovic, James
本研究研究了人源罗伊氏乳杆菌 ATCC PTA 6475 促凋亡作用的分子机制。细胞内酯酶活性、末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记测定和聚（ADP-核糖）聚合酶裂解表明，罗伊氏乳杆菌分泌增强肿瘤坏死因子（TNF）诱导的骨髓白血病来源细胞凋亡的因子。罗伊氏乳杆菌下调核因子 kappa B (NF-kappa B) 依赖性基因产物，介导细胞增殖（Cox-2、细胞周期蛋白 D1）和细胞存活（Bcl-2、Bcl-xL）。罗伊氏乳杆菌以剂量和时间依赖性方式抑制 TNF 诱导的 NF-κ B 激活，包括 NF-κ B 依赖性报告基因表达。罗伊氏乳杆菌稳定 I kappa B α 的降解并抑制 p65 (RelA) 的核转位。尽管 I kappa B α 的磷酸化未受影响，但随后调节 I kappa B α 降解所需的多聚泛素化被罗伊氏乳杆菌废除。此外，罗伊氏乳杆菌通过增强丝裂原激活蛋白激酶 (MAPK) 活性（包括 c-Jun N 末端激酶和 p38 MAPK）来促进细胞凋亡。相反，罗伊氏乳杆菌在 TNF 激活的骨髓细胞中抑制细胞外信号调节激酶 1/2。罗伊氏乳杆菌可能通过抑制 I kappa B α 泛素化和增强促凋亡 MAPK 信号传导，促进激活的免疫细胞凋亡，从而调节细胞增殖。更好地了解罗伊氏乳杆菌介导的细胞凋亡信号通路的影响可能有助于开发未来基于益生菌的治疗方案，以预防结直肠癌和炎症性肠病。
The molecular mechanisms of pro-apoptotic effects of human-derived Lactobacillus reuteri ATCC PTA 6475 were investigated in this study. L. reuteri secretes factors that potentiate apoptosis in myeloid leukemia-derived cells induced by tumour necrosis factor (TNF), as indicated by intracellular esterase activity, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling assays and poly (ADP-ribose) polymerase cleavage. L. reuteri downregulated nuclear factor-kappa B (NF-kappa B)-dependent gene products that mediate cell proliferation (Cox-2, cyclin D1) and cell survival (Bcl-2, Bcl-xL). L. reuteri suppressed TNF-induced NF-kappa B activation, including NF-kappa B-dependent reporter gene expression in a dose-and time-dependent manner. L. reuteri stabilized degradation of I kappa B alpha and inhibited nuclear translocation of p65 (RelA). Although phosphorylation of I kappa B alpha was not affected, subsequent polyubiquitination necessary for regulated I kappa B alpha degradation was abrogated by L. reuteri. In addition, L. reuteri promoted apoptosis by enhancing mitogen-activated protein kinase (MAPK) activities including c-Jun N-terminal kinase and p38 MAPK. In contrast, L. reuteri suppressed extracellular signal-regulated kinases 1/2 in TNF-activated myeloid cells. L. reuteri may regulate cell proliferation by promoting apoptosis of activated immune cells via inhibition of I kappa B alpha ubiquitination and enhancing pro-apoptotic MAPK signalling. An improved understanding of L. reuteri-mediated effects on apoptotic signalling pathways may facilitate development of future probiotics-based regimens for prevention of colorectal cancer and inflammatory bowel disease.