Cellular inhibitor of apoptosis protein 2 controls human colonic epithelial restitution, migration, and Rac1 activation.
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.
Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; jseidelin@dadlnet.dk.
Jakob Benedict
JB
Seidelin
Department of Science, Systems and Models (NSM), Roskilde University, Roskilde, Denmark;
Sylvester
S
Larsen
Department of Pathology, Herlev Hospital, Herlev, Denmark; and.
Dorte
D
Linnemann
Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Ben
B
Vainer
Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark;
Mehmet
M
Coskun
Department of Science, Systems and Models (NSM), Roskilde University, Roskilde, Denmark;
Jesper Thorvald
JT
Troelsen
Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark;
Ole Haagen
OH
Nielsen
D017209:Apoptosis / Q000502:physiology*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D003106:Colon / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D014945:Wound Healing / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C107953:RAC1 protein, human; D053773:Transforming Growth Factor beta1; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D020830:rac1 GTP-Binding Protein
Rac; cIAP2; epithelial restitution; inflammatory bowel disease; intestine; migration; wound healing