title: Inhibition of epithelial cell death by Bcl-2 improved chronic colitis in IL-10 KO mice.
abstract: 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.
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: tmizushima@gesurg.med.osaka-u.ac.jp.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Arakawa
authors.affiliation: Department of Pharmacy, Kure Medical Center/Chugoku Cancer Center, Hiroshima, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Sanada
authors.affiliation: Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Yoshino
authors.affiliation: Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Miyazaki
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Urushima
authors.affiliation: Department of Medical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tsujimoto
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: shimizu.pcb@mri.tmd.ac.jp.
authors.forename: Shigeomi
authors.initials: S
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure
chemical_list: C556062:IL10 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; D016753:Interleukin-10