Background Matrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). In patients with IBD, the intestinal tight junction (TJ) barrier is compromised as characterized by an increase in intestinal permeability. MMP-9 is elevated in intestinal tissue, serum and stool of patients with IBD. Previous studies from our laboratory showed that MMP-9 causes an increase in intestinal epithelial TJ permeability and that the MMP-9 induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in IBD. However, the intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear. Aims The main aim of this study was to further elucidate the molecular mechanisms involved in MMP-9 induced increase in intestinal epithelial TJ permeability using Caco-2 monolayers as an in-vitro model system. Results MMP-9 induced increase in Caco-2 TJ permeability was associated with activation and cytoplasmic-to-nuclear translocation of NF-κB p65. Knocking-down NF-κB p65 by siRNA transfection prevented the MMP-9 induced expression of the NF-κB target gene IL-8, myosin light chain kinase (MLCK) protein expression, and subsequently prevented the increase in Caco-2 TJ permeability. In addition, the effect of MMP-9 on Caco-2 intestinal epithelial TJ barrier function was not mediated by apoptosis or necrosis. Conclusion Our data show that the MMP-9 induced disruption of Caco-2 intestinal epithelial TJ barrier function is regulated by NF-κB pathway activation of MLCK.

Defective intestinal tight junction (TJ) barrier has been implicated in the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), and other inflammatory conditions of the gut. The role of microRNAs (miRNA's or miR's) has also been demonstrated in the last two decades in the pathogenesis of IBD and in the regulation of intestinal TJ barrier function. MiRNAs are non-coding regulators of gene expression at the post-transcription level that have essential role in targeting transcripts encoding proteins of intestinal TJ and their regulators. Many miRNAs have been reported to regulate or deregulate the TJ proteins responsible for the intestinal barrier integrity and intestinal permeability. Many of those miRNAs have been reported to have essential role in the pathogenesis of IBD. In this mini-review, we summarize the results of studies in the last 3 years that implicate miRNAs in the defective TJ barrier in relation to IBD. The therapeutic potential of using specific miRNAs to target the intestinal TJ barrier might be of great insight for IBD therapy.

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