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. Inflamm Bowel Dis 2010 Feb;16(2):320-331
Date
08/29/2009Pubmed ID
19714745Pubmed Central ID
PMC3927407DOI
10.1002/ibd.21066Scopus ID
2-s2.0-73949136139 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
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.
Author List
Sina C, Arlt A, Gavrilova O, Midtling E, Kruse ML, Müerköster SS, Kumar R, Fölsch UR, Schreiber S, Rosenstiel P, Schäfer HAuthor
Emilie Regner MD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsChemokines
Colitis
Colon
Cytokines
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Immediate-Early Proteins
Macrophages
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
NF-kappa B
Neutrophils
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes
