Inhibition of Epithelial Cell Death by Bcl-2 Improved Chronic Colitis in IL-10 KO Mice

• Published in: The American journal of pathology Vol. 183; no. 6; pp. 1936 - 1944
• Main Authors: Mizushima, Tsunekazu, Arakawa, Satoko, Sanada, Yasuaki, Yoshino, Ikuyo, Miyazaki, Dai, Urushima, Hayato, Tsujimoto, Yoshihide, Ito, Toshinori, Shimizu, Shigeomi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2013
• Subjects: Animals; Apoptosis - genetics; Apoptosis - immunology; Chronic Disease; Colitis - genetics; Colitis - immunology; Colitis - metabolism; Colitis - pathology; Epithelial Cells - immunology; Epithelial Cells - metabolism; Epithelial Cells - ultrastructure; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-10 - metabolism; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - ultrastructure; Mice; Mice, Knockout; Pathology; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - immunology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - ultrastructure; Th17 Cells - immunology; Th17 Cells - metabolism; Th17 Cells - ultrastructure
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2013.08.012

IL-10–deficient mice spontaneously develop intestinal inflammation, which has many similarities to Crohn's disease. Several reports suggest that epithelial cell death may increase the severity of colitis; however, decisive evidence is lacking. In the present report, we addressed whether and how epithelial cell death plays a role in the development of chronic colitis. We first examined the morphological characteristics of intestines of IL-10–deficient mice and found two forms of epithelial cell death (typical apoptosis and necrosis-like cell death) in colitis. To elucidate the pathological roles of epithelial cell death, we crossbred IL-10–deficient knockout mice with Bcl-2 transgenic mice, in which the anti-apoptosis protein Bcl-2 was overexpressed in intestinal epithelial cells, but not in immune cells. Epithelial cell–specific Bcl-2 protected IL-10 deficiency–induced colitis and markedly reduced their symptoms. Interestingly, morphological analysis revealed that Bcl-2 suppressed apoptosis and necrosis-like cell death, and better maintained mucosal barrier in IL-10–deficient mice. From the immunological aspect, Bcl-2 did not alter the activation of T-helper cell 1 but inhibited the growth of T-helper cell 17, suggesting that mucosal integrity may control the immune responses. These results provide genetic evidence demonstrating that epithelial cell death is crucial for the development of chronic colitis.