Glutathione Peroxidase in Mouse Inflammatory Bowel Disease and Radiation Protection
Inflammatory bowel disease (IBD) is consisted of Crohn’s disease, which always involves the ileum, and ulcerative colitis, which always involves the colon. About one to two per thousand Americans are diagnosed with IBD each year, and most people diagnosed of Crohn’s disease are between 15-30 years old, when most people diagnosed of ulcerative colitis are in their 30s (www.ccfa.org). Although IBD is not a life-threatening disease, it is painful, needs long-term management, and increases cancer risk in the ileum, the colon, and the rectum.
To better manage this disease, we need to better understand the cause and the progression of this disease. Many animal IBD models have been generated and analyzed for IBD etiology and treatment. Most studied animal IBD models are mouse models for ulcerative colitis. There are only a couple of mouse models for Crohn’s disease, SAMP1/Yit mice and TNFΔARE mice, which overexpress tumor necrosis factor. We have recently generated a new mouse model for Crohn’s disease, by disruption of genes encoding for two Se-dependent glutathione peroxidases (GPXs), Gpx1 and Gpx2. Gpx1/2-double knockout (DKO) mice have more severe ilealitis than colitis, and ten-times more of ileal tumors than colonic tumors.
There are three major factors in IBD etiology: genetic, environmental, and immunological; all have been confirmed in Gpx1/2-DKO mice. Among the mouse inbred lines that we have studied, Gpx1/2-DKO mice on a pure 129/SvJ (129) genetic background have the worst pathology and symptoms; DKO mice on a mixed C57BL/6J (B6) and 129 (B6.129) genetic background still have intermediate symptom and pathology; when B6 DKO mice have very mild disease. This disease is induced by luminal microflora, since germ-free Gpx1/2-DKO mice are disease-free. Although these DKO mice are highly sensitive to certain microflora, the identity of the pathogens remains to be elusive.
Another important environmental factor affecting IBD outcome is the diet. We have found DKO mice on defined diets have much better health than those on commercial rodent chows. Since dietary modulation provides the best health for these DKO mice than many conventional and experimental drugs for IBD, we plan to identify the component of diet that cause ileocolitis.
Increased in reactive oxygen species (ROS) has been observed in inflamed intestinal mucosa in IBD patients, however, it is believed to be caused by inflammation. ROS is also known to activate many pro-inflammatory cytokines presumably by activation of nuclear factor (NF) κB pathway, thus the ROS generated from inflammatory cells adds fuel to the fire and further damage the tissue. We are investigating that whether GPX protects intestinal epithelial cells from oxidative stress, and what are the downstream genes affected by GPX activity.
In addition to the role of GPX in prevention of ileocolitis that we have recently discovered, the antioxidant activity of GPX has long been suspected to protect cells against radiation damage. However, there is little evidence to support this claim. Additionally, whether the radioprotective effect of Amifostine, a small molecule with superoxide dismutase activity, depends on GPX to reduce hydrogen peroxide is not known. We plan to evaluate the role of GPX in protection of intestinal epithelial cells against γ-irradiation in near future.