Cyclic AMP dysregulates intestinal epithelial cell restitution through PKA and RhoA.
Cyclic AMP dysregulates intestinal epithelial cell restitution through PKA and RhoA.
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DOI：
10.1002/ibd.21898
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发表时间：
2012-06
影响因子：
4.9
通讯作者：
Dwinell MB
中科院分区：
文献类型：
--
作者：
Zimmerman NP;Kumar SN;Turner JR;Dwinell MB
粘膜稳态取决于构成生理屏障的细胞与细胞接触的建立和维持。屏障的破坏与炎症性肠病等多种疾病有关。虽然 cAMP 水平升高可通过减少白细胞浸润来限制炎症，但 cAMP 升高对肠上皮修复的影响尚不清楚。激光损伤肠上皮后，通过显微镜检查监测给予咯利普兰的动物或用右旋糖酐硫酸钠（DSS）治疗的小鼠的恢复情况。使用 IEC6 和 T84 细胞进行体外分析，以确定升高的 cAMP 在改变 Rho 依赖性细胞迁移信号通路中的作用。我们发现，用咯利普兰、毛喉素和 cAMP 类似物治疗可减少体外肠上皮细胞迁移。体内细胞成像显示，cAMP 增加导致细胞迁移率降低，边缘的细胞表现出最高的活性。正如预期的那样，cAMP 升高会引起蛋白激酶 A (PKA) 活性增加，进而导致 RhoA 失活和隔离，并减少肌动蛋白重组。 cAMP 对恢复的消融并不限于细胞培养，因为毛喉素和咯利普兰治疗显着降低了两光子共聚焦损伤模型诱导的上皮微伤口闭合。总之，这些数据表明，施用 cAMP 升高剂反而会减少引起损伤的白细胞的浸润，同时还会阻止上皮修复和屏障维持。我们建议使用 cAMP 升高剂治疗严重限制粘膜再上皮化，并且应禁忌用于慢性炎症性肠病。
Mucosal homeostasis is dependent upon the establishment and maintenance of the cell-cell contacts that comprise the physiological barrier. Breaks in the barrier are linked to multiple diseases such as the inflammatory bowel diseases. While increased cAMP levels limit inflammation by decreasing leukocyte infiltration, the effects of elevated cAMP on intestinal epithelial repair are unknown. Restitution in animals administered rolipram was monitored by microscopic examination after laser wounding of the intestinal epithelium or in mice treated with dextran sodium sulfate (DSS). In vitro analysis was conducted using IEC6 and T84 cells to determine the role for elevated cAMP in altering Rho-dependent cellular migration signaling pathways. We show that treatment with rolipram, forskolin, and cAMP-analogs decrease intestinal epithelial cell migration in vitro. In vivo cell imaging revealed that increased cAMP resulted in a decreased cellular migration rate, with cells at the edge displaying the highest activity. As expected, elevated cAMP elicited increased protein kinase A (PKA) activity, in turn resulting in the inactivation and sequestration of RhoA and decreased actin reorganization. The ablation of restitution by cAMP was not restricted to cell culture as forskolin and rolipram treatment significantly decreased epithelial microwound closure induced by the two photon confocal injury model. Together, these data suggest that administration of cAMP elevating agents paradoxically decrease infiltration of damage-causing leukocytes while also preventing epithelial repair and barrier maintenance. We propose that treatment with cAMP elevating agents severely limits mucosal re-epithelialization and should be contraindicated for use in chronic inflammatory bowel disorders.
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影响因子：
7.3
作者：
FROSSARD, N;LANDRY, Y;RUCKSTUHL, M
通讯作者：
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