CD47 regulates collagen I-induced cyclooxygenase-2 expression and intestinal epithelial cell migration.
CD47 regulates collagen I-induced cyclooxygenase-2 expression and intestinal epithelial cell migration.
复制标题
CD47调节胶原I诱导的环氧合酶-2表达和肠上皮细胞迁移。
DOI：
10.1371/journal.pone.0006371
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发表时间：
2009-07-28
期刊：
影响因子：
3.7
通讯作者：
Sjölander A
中科院分区：
文献类型：
--
作者：
Broom OJ;Zhang Y;Oldenborg PA;Massoumi R;Sjölander A
上皮细胞环氧化酶-2 （COX-2）酶表达增加是炎症性肠病和结肠癌的特征性事件。我们在这里报告了新的发现，胶原i诱导肠上皮细胞中COX-2的重新合成被百日咳毒素（PTX）和一种选择性异三聚体g αi3蛋白的抑制肽抑制。这些发现可以通过g蛋白依赖性整合素相关蛋白CD47的调控参与来解释。为了支持这一观点，我们观察到胶原i诱导CD47和α2整合素之间的关联。阻断性抗cd47抗体可降低这种关联，但PTX或对照抗β2抗体不能降低这种关联。此外，针对CD47的阻断抗体，显性CD47阴性或CD47特异性siRNA敲低，显著降低胶原i诱导的COX-2表达。COX-2先前已被证明可调节肠上皮细胞的粘附和迁移。黏附于胶原I的肠细胞形态学分析显示，CD47和α2整合素共定位于富含Rho a和f -肌动蛋白的非凋亡膜泡。阻断CD47抗体PTX和选择性COX-2抑制剂显著抑制了这些水泡的形成。因此，CD47阻断抗体、CD47的siRNA敲低和COX-2抑制剂NS-398显著降低了这些细胞在胶原I包被表面或通过胶原I凝胶的迁移。总之，我们提出的新数据表明，g蛋白依赖的CD47蛋白是胶原i诱导的COX-2表达的关键调节因子和肠上皮细胞迁移的促进因子。
Increased epithelial cell expression of the cyclooxgenase-2 (COX-2) enzyme is a characteristic event of both inflammatory bowel disease and colon cancer. We here report the novel findings that collagen I-induced de novo synthesis of COX-2 in intestinal epithelial cells is inhibited by pertussis toxin (PTX) and by an inhibitory peptide selective for the heterotrimeric Gαi3-protein. These findings could be explained by a regulatory involvement of the G-protein-dependent integrin-associated protein CD47. In support of this notion, we observed a collagen I-induced association between CD47 and α2 integrins. This association was reduced by a blocking anti-CD47 antibody but not by PTX or a control anti-β2 antibody. Furthermore, a blocking antibody against CD47, dominant negative CD47 or specific siRNA knock down of CD47, significantly reduced collagen I-induced COX-2 expression. COX-2 has previously been shown to regulate intestinal epithelial cell adhesion and migration. Morphological analysis of intestinal cells adhering to collagen I revealed a co-localisation of CD47 and α2 integrins to non-apoptotic membrane blebs enriched in Rho A and F-actin. The blocking CD47 antibody, PTX and a selective COX-2 inhibitor, dramatically inhibited the formation of these blebs. In accordance, migration of these cells on a collagen I-coated surface or through a collagen I gel were significantly reduced by the CD47 blocking antibody, siRNA knock down of CD47 and the COX-2 inhibitor NS-398. In conclusion, we present novel data that identifies the G-protein-dependent CD47 protein as a key regulator of collagen I-induced COX-2 expression and a promoter of intestinal epithelial cell migration.