Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark;
Department of Science, Systems and Models (NSM), Roskilde University, Roskilde, Denmark;
Am J Physiol Gastrointest Liver Physiol. 2015 Jan 15;308(2):G92-9. doi: 10.1152/ajpgi.00089.2014. Epub 2014 Nov 13.
Identification of pathways involved in wound healing is important for understanding the pathogenesis of various intestinal diseases. Cellular inhibitor of apoptosis protein 2 (cIAP2) regulates proliferation and migration in nonepithelial cells and is expressed in human colonocytes. The aim of the study was to investigate the role of cIAP2 for wound healing in the normal human colon. Wound tissue was generated by taking rectosigmoidal biopsies across an experimental ulcer in healthy subjects after 5, 24, and 48 h. In experimental ulcers, the expression of cIAP2 in regenerating intestinal epithelial cells (IECs) was increased at the wound edge after 24 h (P < 0.05), returned to normal after reepithelialization, and correlated with the inflammatory reaction in the experimental wounds (P < 0.001). cIAP2 was induced in vitro in regenerating Caco2 IECs after wound infliction (P < 0.01). Knockdown of cIAP2 caused a substantial impairment of the IEC regeneration through inhibition of migration (P < 0.005). cIAP2 overexpression lead to formation of migrating IECs and upregulation of expression of RhoA and Rac1 as well as GTP-activation of Rac1. Transforming growth factor-β1 enhanced the expression of cIAP2 but was not upregulated in wounds in vivo and in vitro. NF-κB and MAPK pathways did not affect cIAP2 expression. cIAP2 is in conclusion a regulator of human intestinal wound healing through enhanced migration along with activation of Rac1, and the findings suggest that cIAP2 could be a future therapeutic target to improve intestinal wound healing.
鉴定参与伤口愈合的途径对于理解各种肠道疾病的发病机制非常重要。细胞凋亡抑制蛋白 2（cIAP2）调节非上皮细胞的增殖和迁移，并且在人结肠细胞中表达。本研究旨在研究 cIAP2 在正常人类结肠中的伤口愈合中的作用。在健康受试者中，在实验性溃疡上进行直肠乙状结肠活检后，于 5、24 和 48 小时产生伤口组织。在实验性溃疡中，cIAP2 在再生的肠上皮细胞（IEC）中的表达在 24 小时后在伤口边缘增加（P <0.05），在再上皮化后恢复正常，并与实验性伤口中的炎症反应相关（P <0.001）。cIAP2 在体外受到损伤后在再生的 Caco2 IEC 中诱导（P <0.01）。cIAP2 的敲低导致 IEC 再生严重受损，通过迁移抑制（P <0.005）。cIAP2 的过表达导致迁移的 IEC 的形成以及 RhoA 和 Rac1 的表达上调以及 Rac1 的 GTP 激活。转化生长因子-β1 增强了 cIAP2 的表达，但在体内和体外的伤口中均未上调。NF-κB 和 MAPK 途径不影响 cIAP2 的表达。cIAP2 是通过增强 Rac1 的迁移以及激活 Rac1 来调节人类肠道伤口愈合的调节剂，研究结果表明 cIAP2 可能是改善肠道伤口愈合的未来治疗靶标。
