Involvement of cellular inhibitor of apoptosis protein 2 (cIAP2) in intestinal wound healing

Abstract

Objective We recently found that cellular inhibitor of apoptosis protein 2 (cIAP2) is upregulated NF-κB dependently in colonic epithelial cells adjacent to epithelial defects in active ulcerative colitis. Since cIAP2 promotes cell migration and proliferation it was investigated if cIAP2 affects colonic wound healing. Methods In vivo wound assay: Healthy subjects had rectosigmoidal biopsies taken with 5 h interval. The second biopsy was taken across the first (index) biopsy. In vitro wound assay: Wounding in confluent Caco2 cell cultures. cIAP2 PCR, immunohistochemistry, and RNA interference was performed. Results Epithelial expression of cIAP2 was absent in index biopsies, but induced in regenerating colonocytes adjacent to the edge of the wound. Wounding in Caco2 cultures gave a 1.9-fold (p<0.04), 1.6-fold (p<0.01), and 1.1-fold (p>0.05) increase in cIAP2 mRNA expression after 2, 6, and 24 h, respectively, the decrease coinciding with wound closure. cIAP2 protein was upregulated in Caco2 cells adjacent to the wound edge. siRNA knockdown of cIAP2 inhibited epithelial restitution (t=18 h wound area 45% of t=0 h (range 36 – 52%) with scramble siRNA; wound area 75% (70 – 95%) with cIAP2 siRNA (p<0.005)). Conclusions cIAP2 is upregulated in wounds of the healthy human intestine and plays an important role for epithelial restitution. Funding: A. P. Møller Foundation, Family Erichsen Memorial Foundation.