Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

Abstract

Liu H, Patel NR, Walter L, Ingersoll S, Sitaraman SV, Garg P. Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc. Am J Physiol Gastrointest Liver Physiol 304: G793-G803, 2013. First published March 7, 2013 doi:10.1152/ajpgi.00249.2012.-Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)-and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSSand S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc. inflammation; dextran sodium sulfate; transgenic mice; IL-8 INFLAMMATORY BOWEL DISEASE (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disease that affects the entire gastrointestinal (GI) tract and the colonic mucosa and is associated with an increased risk for colon cancer. IBD is characterized by relapses (acute flare) and remissions, which are related to genetic basis and involve immune-mediated tissue injury followed by repair. Recent studies have shown that cytokines play a key role in regulating IBD (9, 40). There is increased incidence of IBD in urban areas of industrialized nations (29,42). Matrix metalloproteinases (MMPs) are a group of zinc-dependent enzymes with proteolytic activity against extracellular matrix (ECM) proteins and are also known to play an important role for normal tissue remodeling (47). MMPs have also been shown to be involved in several pathological conditions such as IBD, tumor invasion, and colorect...

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