Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-dependent activation of Rac1 and Cdc42
Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-dependent activation of Rac1 and Cdc42
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DOI：
10.4049/jimmunol.179.12.8112
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发表时间：
2007-12-15
影响因子：
4.4
通讯作者：
Nusrat, Asma
中科院分区：
文献类型：
--
作者：
Babbin, Brian A.;Jesaitis, Algirdas J.;Nusrat, Asma
胃肠道炎症性疾病导致肠上皮屏障以糜烂和溃疡的形式破裂。为了重建上皮屏障，上皮必须有效地迁移以重新密封伤口。许多信号级联参与这一复杂过程的诱导和调节。 N-甲酰肽受体包含一组调节先天免疫反应的 G(i) 偶联受体。此前，我们鉴定了 SK-CO15 模型肠上皮细胞中功能性 N-甲酰肽受体的表达，并观察了这些受体的激活在调节细胞侵袭行为中的作用。在这些研究中，我们进行了甲酰肽受体 1 (FPR) 定位并评估了其在调节肠上皮细胞伤口闭合中的作用。使用最近开发的特异性单克隆抗 FPR Ab 进行的免疫定位研究表明，其沿着正常人结肠上皮的隐窝上皮细胞的侧膜定位。使用经典 FPR 激动剂 fMLF 的体外研究表明，FPR 激活显着增强模型肠上皮细胞的恢复，并且 FPR 沿着板状伪足和丝状伪足挤压中的肌动蛋白丝定位。细胞迁移的增加与 PI3K、Racl 和 Cdc42 的激活相关。 PI3K 活性的药物抑制消除了 fMLF 诱导的伤口闭合增加以及 Rac1 和 Cdc42 的激活。使用药物抑制剂和显性失活突变体抑制 Rac1 和 Cdc42 也抑制了 fMLF 诱导的细胞迁移增加。总而言之，这些结果支持 FPR 刺激通过 PI3K 依赖性激活 Rac1 和 Cdc42 来增强肠上皮细胞恢复的新作用。
Inflammatory disorders of the gastrointestinal tract result in the breakdown of the intestinal epithelial barrier in the form of erosion and ulceration. To reestablish the epithelial barrier, the epithelium must efficiently migrate to reseal wounds. Numerous signaling cascades are involved in the induction and regulation of this complex process. N-formyl peptide receptors comprise a group of G(i)-coupled receptors that regulate innate immune responses. Previously, we identified the expression of functional N-formyl peptide receptors in model SK-CO15 intestinal epithelial cells and observed a role for activation of these receptors in regulating cellular invasive behavior. In these studies, we performed formyl peptide receptor-1 (FPR) localization and evaluated its role in regulating intestinal epithelial cell wound closure. Immunolocalization studies using a recently developed specific monoclonal anti-FPR Ab demonstrated its localization along the lateral membrane of crypt epithelial cells in normal human colonic epithelium. In vitro studies using the classical FPR agonist fMLF showed that FPR activation significantly enhances model intestinal epithelial cell restitution and that FPR localized along actin filaments in lamellipodial and filopodial extrusions. The increase in cell migration was associated with activation of PI3K, Racl, and Cdc42. Pharmacologic inhibition of PI3K activity abrogated the fMLF-induced increase in wound closure and activation of both Rac1 and Cdc42. Inhibition of Rac1 and Cdc42 using pharmacologic inhibitors and dominant negative mutants also inhibited the fMLF-induced increase in cell migration. Taken together, theses results support a novel role for FPR stimulation in enhancing intestinal epithelial cell restitution through PI3K-dependent activation of Rac1 and Cdc42.