Positive role of CCAAT/enhancer-binding protein homologous protein, a transcription factor involved in the endoplasmic reticulum stress response in the development of colitis.

Abstract

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-1alpha, and Caspase-11 (a positive regulator of interleukin-1beta production) in the intestine was induced with the development of colitis, and this induction was suppressed in CHOP-null mice. ERO-1alpha 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-1alpha, interleukin-1beta production via the induction of Caspase-11, and intestinal mucosal cell apoptosis.

• Authors: Takushi Namba, Ken-Ichiro Tanaka, Yosuke Ito, Tomoaki Ishihara, Tatsuya Hoshino, Tomomi Gotoh, Motoyoshi Endo, Keizo Sato, Tohru Mizushima
• Journal: The American journal of pathology (Am J Pathol) Vol. 174 Issue 5 Pg. 1786-98 (May 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19359519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ddit3 protein, mouse
• Interleukin-1beta
• Macrophage-1 Antigen
• RNA, Messenger
• Reactive Oxygen Species
• Thiobarbituric Acid Reactive Substances
• Transcription Factor CHOP
• Peroxidase
• Casp4 protein, mouse
• Caspases
• Caspases, Initiator

Topics

• Animals
• Apoptosis (physiology)
• Caspases (genetics, metabolism)
• Caspases, Initiator
• Colitis (chemically induced, etiology, pathology)
• Endoplasmic Reticulum (metabolism)
• Immunoblotting
• Interleukin-1beta (genetics, metabolism)
• Intestinal Mucosa (cytology, metabolism)
• Lipid Peroxidation
• Macrophage-1 Antigen (genetics, metabolism)
• Macrophages (cytology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oxidative Stress
• Peroxidase (metabolism)
• RNA, Messenger (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Thiobarbituric Acid Reactive Substances (metabolism)
• Transcription Factor CHOP (physiology)