Novel anti-inflammatory functions for endothelial and myeloid cyclooxygenase-2 in a new mouse model of Crohn's disease.

Abstract

Cyclooxygenase-2 (COX-2) is an important regulator of inflammation implicated in the development of a variety of diseases, including inflammatory bowel disease (IBD). However, the regulation of intestinal inflammation by COX-2 is poorly understood. We previously reported that COX-2(-/-) mice fed a cholate-containing high-fat (CCHF) diet had high mortality of unknown mechanisms attributable to severe intestinal inflammation in the ileo-ceco-colic junction that presented characteristics similar to Crohn's disease (CD). To further characterize the role of COX-2 in intestinal inflammation, we established cell-specific conditional COX-2(-/-) mice. Endothelial cell-specific (COX-2(-E/-E)) and myeloid cell-specific (COX-2(-M/-M)) COX-2(-/-) mice, but not wild-type mice, on the CCHF diet developed localized CD-like pathology at the ileo-ceco-colic junction that was associated with cellular infiltration, increased expression of myeloperoxidase and IL-5, and decreased IL-10 expression. The CD-like pathology in COX-2(-E/-E) mice was also accompanied by increased expression of cytokines (IL-6, TNF-alpha, and INF-gamma), compared with wild-type mice and COX-2(-M/-M) mice. In contrast, the ileo-ceco-colic inflammation in COX-2(-M/-M) mice was associated with more pronounced infiltration of granulocytes and macrophages than COX-2(-E/-E) mice. COX-2(-ME/-ME) (COX-2(-M/-M) x COX-2(-E/-E)) mice on the CCHF diet developed CD-like pathology in the ileo-ceco-colic junction reminiscent of total COX-2(-/-) mice on CCHF diet and wild-type mice on CCHF diet treated with COX-2 inhibitor, celecoxib. The pathology of diet-mediated ileo-ceco-colic inflammation in COX-2(-/-) mice offers an excellent model system to elucidate the protective roles of endothelial and myeloid COX-2 and the molecular pathogenesis of CD.

• Authors: Junji Watanabe, James A Lin, Ajay J Narasimha, Ani Shahbazian, Tomo-O Ishikawa, Martin G Martin, Harvey R Herschman, Srinivasa T Reddy
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 298 Issue 6 Pg. G842-50 (Jun 2010) ISSN: 1522-1547 [Electronic] United States
• PMID: 20299600 (Publication Type: Journal Article)

Chemical References

• Caenorhabditis elegans Proteins
• Cholates
• DIE-1 protein, C elegans
• Dietary Fats
• Transcription Factors
• Ptgs2 protein, mouse
• Cyclooxygenase 2

Topics

• Animals
• Caenorhabditis elegans Proteins
• Cecum (pathology)
• Cholates (adverse effects)
• Colon, Ascending (pathology)
• Crohn Disease (genetics, metabolism, pathology)
• Cyclooxygenase 2 (genetics, metabolism)
• Dietary Fats (adverse effects)
• Disease Models, Animal
• Endothelial Cells (enzymology, metabolism)
• Female
• Ileum (pathology)
• Inflammation (enzymology, pathology)
• Macrophages (cytology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Cells (enzymology, metabolism)
• Transcription Factors