Positive Role of CCAAT/Enhancer-Binding Protein Homologous Protein, a Transcription Factor Involved in the Endoplasmic Reticulum Stress Response in the Development of Colitis

• Published in: The American journal of pathology Vol. 174; no. 5; pp. 1786 - 1798
• Main Authors: Namba, Takushi, Tanaka, Ken-Ichiro, Ito, Yosuke, Ishihara, Tomoaki, Hoshino, Tatsuya, Gotoh, Tomomi, Endo, Motoyoshi, Sato, Keizo, Mizushima, Tohru
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01-05-2009; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Apoptosis - physiology; Biological and medical sciences; Caspases - genetics; Caspases - metabolism; Colitis - chemically induced; Colitis - etiology; Colitis - pathology; Endoplasmic Reticulum - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Immunoblotting; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Intestinal Mucosa - cytology; Intestinal Mucosa - metabolism; Lipid Peroxidation; Macrophage-1 Antigen - genetics; Macrophage-1 Antigen - metabolism; Macrophages - cytology; Macrophages - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Other diseases. Semiology; Oxidative Stress; Pathology; Peroxidase - metabolism; Reactive Oxygen Species - metabolism; Regular; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thiobarbituric Acid Reactive Substances - metabolism; Transcription Factor CHOP - physiology; Transcription factor C/EBPα; Pathogenesis; Rodentia; Homology; Stress; Vertebrata; Mammalia; Mouse; Animal; Genetics; Digestive diseases; Intestinal disease; Colitis; Endoplasmic reticulum
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.080864

Although recent reports suggest that the endoplasmic reticulum (ER) stress response is induced in association with the development of inflammatory bowel disease, its role in the pathogenesis of inflammatory bowel disease remains unclear. The CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a transcription factor that is involved in the ER stress response, especially ER stress-induced apoptosis. In this study, we found that experimental colitis was ameliorated in CHOP-null mice, suggesting that CHOP exacerbates the development of colitis. The mRNA expression of Mac-1 ( CD11b , a positive regulator of macrophage infiltration), Ero-1 α , and Caspase-11 (a positive regulator of interleukin-1β production) in the intestine was induced with the development of colitis, and this induction was suppressed in CHOP-null mice. ERO-1α is involved in the production of reactive oxygen species (ROS); an increase in ROS production, which is associated with the development of colitis in the intestine, was suppressed in CHOP-null mice. A greater number of apoptotic cells in the intestinal mucosa of wild-type mice were observed to accompany the development of colitis compared with CHOP-null mice, suggesting that up-regulation of CHOP expression exacerbates the development of colitis. Furthermore, this CHOP activity appears to involve various stimulatory mechanisms, such as macrophage infiltration via the induction of Mac-1, ROS production via the induction of ERO-1α, interleukin-1β production via the induction of Caspase-11, and intestinal mucosal cell apoptosis.