Z Gastroenterol 2009; 47 - V32
DOI: 10.1055/s-0029-1241249

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-kappaB

A Arlt 1, C Sina 1, O Gavrilova 2, E Midtling 2, ML Kruse 1, M Großmann 1, R Kumar 3, UR Fölsch 1, S Schreiber 2, P Rosenstiel 2, H Schäfer 1
  • 1UKSH Campus Kiel, Klinik für Allgemeine Innere Medizin, Kiel, Germany
  • 2UKSH Campus Kiel, Inst. für Klinische Molekularbiologie, Kiel, Germany
  • 3Mayo Clinic, Depts. of Medicine, Biochemistry and Molecular Biology, Rochester, United States

Aims: Inflammatory bowel diseases (IBD) result from environmental and genetic factors and are characterized by an imbalanced immune response in the gut and deregulated activation of the transciption factor NF-kappaB.

Goal: Addressing the role of the stress associated early response gene IEX-1/IER3 (murine homologue: gly96) in the regulation of NF-kappaB in IBD, we used the 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 continously with 4% DSS (6 days) and repeatedly with 2% DSS (28 days) for inducing an acute and chronic colitis, respectively. In addition to clinical and histological exploration, colon organ culture and bone marrow derived cells (BMCs) were analysed for chemo-/cytokine expression and NF-kappaB 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 leucocytes and marked histological changes. The expression of pro-inflammatory chemo- and cytokines was higher in the colon of DSS treated gly96/iex-1 -/- mice, and the NF-kappaB activation was enhanced particularly in the distal colon. In cultured BMCs from gly96/iex-1 -/- mice, Pam3Cys4 treatment induced expression of pro-inflammatory mediators to higher degree than in gly96/iex-1 +/+ BMCs, along with enhanced NF-kappaB 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 anti-inflammatory activity via its NF-kappaB-counterregulatory effect.