The roal of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia
The roal of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia
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DOI：
10.1186/1471-230x-10-82
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发表时间：
2010-07-16
影响因子：
2.4
通讯作者：
Fukata, Masayuki
中科院分区：
文献类型：
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作者：
Hernandez, Yasmin;Sotolongo, John;Fukata, Masayuki
背景资料：我们以前发现TLR 4缺陷（TLR 4-/-）小鼠表现出粘膜PGE表达降低（2），并对结肠炎相关肿瘤形成有保护作用。然而，目前尚不清楚PGE（2）是否是促进肠道肿瘤发生的TLR 4信号下游的中心因子。为了进一步阐明涉及TLR 4介导的肠道肿瘤发生的关键下游途径，我们检测了外源性给予TLR 4-/-小鼠PGE（2）的影响，以观察PGE（2）是否绕过了结肠炎相关肿瘤发生的保护作用。方法：小鼠结肠炎相关肿瘤通过氧化偶氮甲烷（AOM）注射诱导，然后进行两个周期的葡聚糖硫酸钠（DSS）治疗。在结肠炎恢复期每天灌胃给予两种不同剂量的PGE（2）（高剂量组，200 μ g，n = 8;低剂量组，100 μ g，n = 6）。另一组在DSS治疗期间给予PGE（2）（200 μ g，n = 5）。炎症和发育不良进行了组织学评估。结果：在PBS处理的对照小鼠中，WT小鼠（n = 13）的平均肿瘤数高于TLR 4-/-小鼠（n = 7）。高剂量PGE（2）处理引起上皮细胞增殖增加，但低剂量PGE（2）处理不引起。PBS处理的TLR 4-/-小鼠中有28.6%发生发育异常（肿瘤/动物：0.4 +/-0.2）。相比之下，高剂量组的75.0%（肿瘤/动物：1.5 +/-1.2，P < 0.05）和低剂量组的33.3%（肿瘤/动物：0.3 +/-0.5）在TLR 4-/-小鼠中发展发育异常。高剂量PGE（2）治疗也增加了肿瘤的大小。在结肠炎急性期和恢复期，PGE（2）治疗对内源性前列腺素类合成的影响不同。外源性给予PGE（2）增加结肠炎相关的肿瘤发生，但这只发生在恢复期。最后，PGE 2处理后，AR和考克斯-2的表达增加，从而诱导EGFR活化，形成正反馈机制，扩增黏膜考克斯-2。结论：PGE（2）是TLR 4介导的肠道肿瘤发生的重要下游分子。
Background: We have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE (2) and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE (2) is the central factor downstream of TLR4 signaling that promotes intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE (2) in TLR4-/-mice to see if PGE (2) bypasses the protection from colitis-associated tumorigenesis.Method: Mouse colitis-associated neoplasia was induced by azoxymethane (AOM) injection followed by two cycles of dextran sodium sulfate (DSS) treatment. Two different doses of PGE (2) (high dose group, 200 mu g, n = 8; and low dose group, 100 mu g, n = 6) were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE (2) during DSS treatment (200 mu g, n = 5). Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR) expression, prostanoid synthesis, and EGFR activation were analyzed.Results: In control mice treated with PBS, the average number of tumors was greater in WT mice (n = 13) than in TLR4-/-mice (n = 7). High dose but not low dose PGE (2) treatment caused an increase in epithelial proliferation. 28.6% of PBS-treated TLR4-/-mice developed dysplasia (tumors/animal: 0.4 +/- 0.2). By contrast, 75.0% (tumors/animal: 1.5 +/- 1.2, P < 0.05) of the high dose group and 33.3% (tumors/animal: 0.3 +/- 0.5) of the low dose group developed dysplasia in TLR4-/-mice. Tumor size was also increased by high dose PGE (2) treatment. Endogenous prostanoid synthesis was differentially affected by PGE (2) treatment during acute and recovery phases of colitis. Exogenous administration of PGE (2) increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE 2 treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.Conclusions: These results highlight the importance of PGE (2) as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.