The pro-inflammatory mediator leukotriene D4 induces phosphatidylinositol 3-kinase and Rac-dependent migration of intestinal epithelial cells
The pro-inflammatory mediator leukotriene D4 induces phosphatidylinositol 3-kinase and Rac-dependent migration of intestinal epithelial cells
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DOI：
10.1074/jbc.m409811200
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发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Sjölander, A
中科院分区：
文献类型：
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作者：
Paruchuri, S;Broom, O;Sjölander, A
炎症性肠病与患结肠癌的风险增加有关。促炎白三烯D-4 （LTD4）可能在这一过程中发挥作用，因为LTD4可以在非转化肠上皮细胞中发出增殖和存活增加的信号，这是癌细胞的两个标志。在这里，我们发现LTD4也可以在这些细胞中发出增加运动性的信号。同时，我们发现LTD4诱导Rac同时瞬时增加10倍，但Cdc42活性没有增加。LTD4激活Rac GDP/GTP交换因子Vav2的能力也支持了这些数据。此外，LTD4触发了磷脂酰肌醇3-激酶（PI3K）磷酸化的3倍瞬时增加，PI3K可能是Vav2/Rac信号通路的上游激活因子。Rac的激活可被PI3K抑制剂LY294002和wortmannin以及PI3K激酶阴性突变体或Vav2的显性阴性形式转染阻断。此外，Rac被发现在由pi3k依赖机制形成的ltd4生成的膜褶中与肌动蛋白共定位。由此可见，对PI3K和Rac信号通路的抑制也阻断了ltd4诱导的肠细胞迁移。目前的数据表明，炎症介质如LTD4不仅可以增加非转化肠上皮细胞的增殖和存活，而且还可以通过PI3K/Rac信号通路触发这些细胞的运动反应。这些数据表明炎症介质参与炎症性肠病增加结肠癌发展风险的过程。
Inflammatory bowel diseases are associated with increased risk of developing colon cancer. A possible role of the pro-inflammatory leukotriene D-4 (LTD4) in this process has been implicated by the findings that LTD4 can signal increased proliferation and survival, both hallmarks of a cancer cell, in non-transformed intestinal epithelial cells. Here we make the novel finding that LTD4 can also signal increased motility in these cells. In parallel, we found that LTD4 induced a simultaneous transient 10-fold increase in Rac but not Cdc42 activity. These data were also supported by the ability of LTD4 to activate the Rac GDP/GTP exchange factor Vav2. Further, LTD4 triggered a 3-fold transient increase in phosphatidylinositol 3-kinase (PI3K) phosphorylation, a possible upstream activator of the Vav2/Rac signaling pathway. The activation of Rac was blocked by the PI3K inhibitors LY294002 and wortmannin and by transfection of a kinase-negative mutant of PI3K or a dominant-negative form of Vav2. Furthermore, Rac was found to co-localize with actin in LTD4-generated membrane ruffles that were formed by a PI3K-dependent mechanism. In accordance, the inhibition of the PI3K and Rac signaling pathway also blocked the LTD4-induced migration of the intestinal cells. The present data reveal that an inflammatory mediator such as LTD4 cannot only increase proliferation and survival of non-transformed intestinal epithelial cells but also, via a PI3K/Rac signaling pathway, trigger a motile response in such cells. These data demonstrate the capacity of inflammatory mediators to participate in the process by which inflammatory bowel conditions increase the risk for colon cancer development.