Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis.
Inflammatory bowel diseases, chronic inflammatory disorders, have been strongly linked with an increased risk of the development of colorectal cancer. Understanding the etiology of these diseases is pivotal for the improvement of currently available strategies to fight against inflammatory bowel disease, and more importantly, to prevent colorectal cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been known to be a transcriptional factor which plays a crucial role in cytoprotection against inflammation, as well as oxidative and electrophilic stresses. The aim of this study is to investigate the role of Nrf2 in the regulation of dextran sulfate sodium (DSS)-induced experimental colitis in mice. Nrf2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis following 1 week of oral administration of 1% DSS. The increased severity of colitis in Nrf2(-/-) mice was found to be associated with decreased expression of antioxidant/phase II detoxifying enzymes including heme-oxygenase-1, NAD(P)H-quinone reductase-1, UDP-glucurosyltransferase 1A1, and glutathione S-transferase Mu-1. In addition, proinflammatory mediators/cytokines such as COX-2, inducible nitric oxide, interleukin 1beta, interleukin 6, and tumor necrosis factor alpha were significantly increased in the colonic tissues of Nrf2(-/-) mice compared with their wild-type (Nrf2+/+) counterparts. In summary, we show for the first time that mice lacking Nrf2 are more susceptible to DSS-induced colitis. Our data suggests that Nrf2 could play an important role in protecting intestinal integrity, through regulation of proinflammatory cytokines and induction of phase II detoxifying enzymes.
Khor
Tin Oo
TO
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Huang
Mou-Tuan
MT
Kwon
Ki Han
KH
Chan
Jefferson Y
JY
Reddy
Bandaru S
BS
Kong
Ah-Ng
AN
D000818:Animals; D001344:Autopsy; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000453:epidemiology; D017931:DNA Primers; D016264:Dextran Sulfate / Q000633:toxicity*; D004198:Disease Susceptibility; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics; D016133:Polymerase Chain Reaction
D017931:DNA Primers; D051267:NF-E2-Related Factor 2; D016264:Dextran Sulfate