HOST NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR-2 DEFENSE SYSTEM DETERMINES THE OUTCOME OF DEXTRAN SULFATE SODIUM-INDUCED COLITIS IN MICE

Abstract

Administration of dextran sulfate sodium (DSS) in drinking water led to significant bout of colitis simulating ulcerative colitis of human. However, colitis usually developed 5 - 7 days after DSS administration. Therefore, we hypothesized host defense system might protect colitis up to 5 days of DSS administration. 2.5% DSS-induced colitis were administered to C57BL/6 mice and sequential measurements of pathology, cyclooxygenase-2 (COX-2), nuclear factor-kappa B (NF-kappa B), heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO1), gamma-glutamylcysteine synthetase (gamma-GCS), nuclear factor erythroid 2-related factor-2 (Nrf2), and keap1 were done at 2, 6, 12, 24, 48, 96, 120, and 168 hour of DSS administration, respectively. DSS-induced colitis was repeated in either COX-2(-/-) or Nrf2(-/-) mice. On serial pathological analysis, significant colitis was noted after 120 h of DSS administration, during which both activations of COX-2/NF-kappa B and HO-1/Nrf2 were noted. Nrf2 activations after keap1 inactivation led to significant increases in HO-1 after 168 hours of DSS administration, when NF-kappa B nuclear translocation was noted. Significantly attenuated colitis was noted in DSS-challenged COX-2(-/-) mice, in which the levels of HO-1 were significantly decreased compared to DSS-challenged WT littermates (p < 0.01), while the levels of NQO1 were significantly increased. On DSS administration to Nrf2(-/-) mice, colitis was significantly aggravated (p < 0.01), in which the expressions of COX-2 as well as expressions of HO-1 and gamma-GCS were significantly increased (p < 0.01). Reciprocal activations of inflammatory and antioxidative defense signaling after DSS administration might be prerequisite to make intestinal homeostasis and host defense Nrf2 system can determine colitis.