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 NF‐κB

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‐κB. Addressing the potential role of gly96/iex‐1 in the regulation of NF‐κB in IBD,...

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Published in:Inflammatory bowel diseases 2010-02, Vol.16 (2), p.320-331
Main Authors: Sina, Christian, Arlt, Alexander, Gavrilova, Olga, Midtling, Emilie, Kruse, Marie‐Luise, Müerköster, Susanne Sebens, Kumar, Rajiv, Fölsch, Ulrich R., Schreiber, Stefan, Rosenstiel, Philip, Schäfer, Heiner
Format: Article
Language:English
Subjects:
cytokines
feedback regulation
intestinal inflammation
signal transduction
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Summary: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‐κB. Addressing the potential role of gly96/iex‐1 in the regulation of NF‐κB in IBD, we used the dextran sodium sulfate (DSS) colitis model in mice in which the gly96/iex‐1 gene had been deleted. Methods: C57BL/6 mice of gly96/iex‐1−/− or gly96/iex‐1+/+ 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‐κB activation. Results: Compared to wildtype littermates, gly96/iex‐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 gly96/iex‐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 gly96/iex‐1−/− mice, and the NF‐κB activation was enhanced particularly in the distal colon. In cultured BMCs from gly96/iex‐1−/− mice, Pam3Cys4 treatment induced expression of proinflammatory mediators to a higher degree than in gly96/iex‐1+/+ BMCs, along with greater NF‐κB 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‐κB‐counterregulatory effect. (Inflamm Bowel Dis 2009;)
ISSN:1078-0998
1536-4844
DOI:10.1002/ibd.21066