Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine
Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine
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DOI：
10.1053/j.gastro.2006.06.017
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发表时间：
2006-09-01
期刊：
影响因子：
29.4
通讯作者：
Abreu, Maria T.
中科院分区：
文献类型：
--
作者：
Fukata, Masayuki;Chen, Anli;Abreu, Maria T.
背景和目标：我们最近发现，Toll样受体4（TLR 4）或其衔接分子MyD 88缺陷的小鼠在葡聚糖硫酸钠（DSS）诱导的损伤后，与野生型（WT）小鼠相比，结肠炎的体征增加。我们希望验证环氧化酶2（Cox 2）衍生的前列腺素E-2（PGE（2））在TLR 4相关粘膜修复中的重要性这一假设。研究方法：考克斯-2表达通过实时聚合酶链反应、免疫组织化学、蛋白质印迹和荧光素酶报告基因构建体进行分析。小干扰RNA用于抑制MyD 88的表达。给予TLR 4-/-或WT小鼠2.5%DSS 7天。分别用溴脱氧尿苷染色和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法评估细胞增殖和凋亡。PGE（2）口服给药DSS治疗的小鼠。结果：肠上皮细胞系上调考克斯-2表达的TLR 4和MyD 88依赖的方式。选择性考克斯-2抑制剂或针对MyD 88的小干扰RNA可阻断脂多糖介导的PGE（2）产生刺激。DSS损伤后，考克斯-2表达仅在WT小鼠中增加。与WT小鼠相比，TLR 4-/-小鼠在DSS损伤后具有显著降低的增殖和增加的凋亡。TLR 4-/-小鼠补充PGE（2）可改善结肠炎的临床体征，并使增殖和凋亡恢复至WT值。改善上皮修复的机制可能是通过PGE（2）依赖性激活表皮生长因子受体。结论：我们描述了TLR 4信号传导和考克斯-2在肠道中的表达之间的重要联系。TLR 4和MyD 88信号传导是受损肠中最佳增殖和抗凋亡保护所必需的。虽然TLR 4信号在短期内是有益的，但通过TLR 4的慢性信号可能会降低结肠炎相关癌症的阈值。
Background & Aims: We recently showed that mice deficient in Toll-like receptor 4 (TLR4) or its adapter molecule MyD88 have increased signs of colitis compared with wild-type (WT) mice after dextran sodium sulfate (DSS)-induced injury. We wished to test the hypothesis that cyclooxygenase 2 (Cox2)-derived prostaglandin E-2 (PGE(2)) is important in TLR4-related mucosal repair. Methods: Cox-2 expression was analyzed by real-time polymerase chain reaction, immunohistochemistry, Western blotting, and luciferase reporter constructs. Small interfering RNA was used to inhibit expression of MyD88. TLR4-/- or WT mice were given 2.5% DSS for 7 days. Proliferation and apoptosis were assessed using bromodeoxyuridine staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays, respectively. PGE(2) was given orally to DSS-treated mice. Results: intestinal epithelial cell lines up-regulated Cox-2 expression in a TLR4- and MyD88-dependent fashion. Lipopolysaccharide-mediated stimulation of PGE(2) production was blocked by a selective Cox-2 inhibitor or small interfering RNA against MyD88. After DSS injury, Cox-2 expression increased only in WT mice. TLR4-/- mice have significantly reduced proliferation and increased apoptosis after DSS injury compared with WT mice. PGE(2) supplementation of TLR4-/- mice resulted in improvement in clinical signs of colitis and restoration of proliferation and apoptosis to WT values. The mechanism for improved epithelial repair may be through PGE(2)-dependant activation of the epidermal growth factor receptor. Conclusions: We describe an important link between TLR4 signaling and Cox-2 expression in the gut. TLR4 and MyD88 signaling are required for optimal proliferation and protection against apoptosis in the injured intestine. Although TLR4 signaling is beneficial in the short term, chronic signaling through TLR4 may lower the threshold for colitis-associated cancer.