A wide array of phase II detoxifying or antioxidant enzymes constitute a fundamental cellular defense system against oxidative and electrophilic stresses. The major cellular cytoprotective enzymes include heme oxygenase-1 (HO-1), NADPH:quinone oxidoreductase (NQO-1), and glutamate cysteine ligase (GCL). Inappropriately elevated expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been implicated in inflammation and tumor promotion. However, the interactions/cross-talks between cellular signaling pathways responsible for antioxidant gene induction and those mediating proinflammatory protein expression are not fully understood. In an attempt to investigate the possible role of antioxidant enzymes in protecting against inflammatory damage, we utilized the dextran sulfate sodium (DSS)-induced colitis mouse model. Treatment of male ICR mice with 2.5% of DSS in drinking water for 7 days caused inflammatory injury in colonic mucosa which was accompanied by significant induction of COX-2 and iNOS. The DNA binding activities of NF-\#954;B and AP-1, two major transcription factors known to upregulate proinflammatory gene expression, were elevated following DSS administration. Degradation of I\#954;B\#945;, the NF-\#954;B repressor, was also more prominent in the DSS-treated mouse colon. In addition, DSS treatment accelerated phosphorylation of c-Jun N-terminal kinase (JNK) and Akt. When the COX-2 knock out (cox-2 -/-) mice were treated with DSS, the colonic damage was less severe than that observed in wild-type mice. The promoter regions of HO-1, NQO-1, and GCL harbor the specific sequence named antioxidant response elements (ARE) or electrophile reponse elements (EpRE) to which the transcription factor Nrf2 binds preferentially. The transcriptional activity of Nrf2, as measured by use of ARE-hPAP (human placental alkaline phosphatase) transgenic reporter mice, was gradually increased in the colon as a consequence of DSS treatment. In the cox-2 -/- mice, DSS-induced HO-1 expression was significantly decreased compared with that observed in cox-2 +/+ animals. The nrf2-/- mice were more prone to DSS-induced inflammatory damage compared with nrf2+/+ mice. Taken together, these results suggest that Nrf2-ARE driven induction of HO-1 expression confers adaptive survival response to DSS-induced inflammation in mouse colon.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3528.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO