Ablation of Gly96/Immediate Early Gene-X1 (gly96/iex-1) Aggravates DSS-Induced Colitis in Mice: Role for gly96/iex-1 in the Regulation of NFKB

Background: Inflammatory bowel diseases (IBDs) result from environmental and genetic factors and are characterized by an imbalanced immune response in the gut and deregulated activation of the transcription factor NF-kappa B. Addressing the potential role of gly96/iex-1 in the regulation of NF-kappa B in IBD, we used the dextran sodium sulfate (DSS) colitis model in mice in which the gly%liex-1 gene had been deleted. Methods: C57BL/6 mice of gly961iex-1(-/-) or g1y961iex-I+/+ genotype were treated continuously with 4% DSS (5 days) and repeatedly with 2% DSS (28 days) for inducing acute and chronic colitis, respectively. In addition to clinical and histological exploration, colon organ culture and bone marrow-derived cells (BMCs) were analyzed for chemo/cytokine expression and NF-kappa B activation. Results: Compared to wildtype littermates, gly961ie.1c-1(-/-) mice exhibited an aggravated phenotype of both acute and chronic colitis, along with a greater loss of body weight and colon length. Colonic endoscopy revealed a higher degree of hyperemia, edema, and bleeding in gly,961iex-1(-/-) mice, and immunohistochemistry detected massive mucosal infiltration of leukocytes and marked histological changes. The expression of proinflammatory chemo- and cytokines was higher in the colon of DSS-treated gly96liex1(-/-) mice, and the NF-kappa B lactivation was enhanced particularly in the distal colon. In cultured BMCs from g1y961iev-1(-/-) mice, Pam(3)Cys(4) treatment induced expression of proinflammatory mediators to a higher degree than in g1y961ie.v-1(+/+) BMCs, along with greater NF-kappa B activation. Conclusions: Based on the observation that genetic ablation of gly96/iex-1 triggers intestinal inflammation in mice, we demonstrate for the first time that gly96/iex-1 exerts strong antiinflammatory activity via its NF-kappa B-counterregulatory effect.