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.
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-kappaB. Addressing the potential role of gly96/iex-1 in the regulation of NF-kappaB 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-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 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-kappaB activation was enhanced particularly in the distal colon. In cultured BMCs from gly96/iex-1(-/-) mice, Pam(3)Cys(4) treatment induced expression of proinflammatory mediators to a higher degree than in gly96/iex-1(+/+) BMCs, along with greater 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 antiinflammatory activity via its NF-kappaB-counterregulatory effect.
Sina
Christian
C
Institute of Clinical Molecular Biology, UKSH-Campus Kiel, Kiel, Germany.
Arlt
Alexander
A
Laboratory of Molecular Gastroenterology & Hepatology, Department of General Medicine, UKSH-Campus Kiel, Kiel, Germany.
Gavrilova
Olga
O
Institute of Clinical Molecular Biology, UKSH-Campus Kiel, Kiel, Germany.
Midtling
Emilie
E
Institute of Clinical Molecular Biology, UKSH-Campus Kiel, Kiel, Germany.
Kruse
Marie-Luise
ML
Laboratory of Molecular Gastroenterology & Hepatology, Department of General Medicine, UKSH-Campus Kiel, Kiel, Germany.
Müerköster
Susanne Sebens
SS
Laboratory of Molecular Gastroenterology & Hepatology, Department of General Medicine, UKSH-Campus Kiel, Kiel, Germany.
Kumar
Rajiv
R
Departments of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
Fölsch
Ulrich R
UR
Laboratory of Molecular Gastroenterology & Hepatology, Department of General Medicine, UKSH-Campus Kiel, Kiel, Germany.
Schreiber
Stefan
S
Institute of Clinical Molecular Biology, UKSH-Campus Kiel, Kiel, Germany.
Rosenstiel
Philip
P
Institute of Clinical Molecular Biology, UKSH-Campus Kiel, Kiel, Germany.
Schäfer
Heiner
H
Laboratory of Molecular Gastroenterology & Hepatology, Department of General Medicine, UKSH-Campus Kiel, Kiel, Germany.
D000818:Animals; D018925:Chemokines / Q000502:physiology; D003092:Colitis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000502:physiology
D018925:Chemokines; D016207:Cytokines; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D016328:NF-kappa B