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. doi: 10.1002/ibd.21066.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokines / physiology
  • Colitis / genetics*
  • Colitis / pathology
  • Colitis / physiopathology
  • Colon / pathology
  • Cytokines / physiology
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / physiology*
  • Macrophages / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • NF-kappa B / physiology*
  • Neutrophils / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / physiology

Substances

  • Chemokines
  • Cytokines
  • IEX-1 protein, mouse
  • Immediate-Early Proteins
  • NF-kappa B