Abstract
BackgroundMatrix 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.AimsThe 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.ResultsMMP-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.ConclusionOur 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.
Highlights
The intestinal epithelium is a single layer of cells within the gut lumen that serves an important protective function
Previous studies from our laboratory showed that matrix metalloproteinases (MMPs)-9 causes an increase in intestinal epithelial tight junction barrier (TJ) permeability and that the Matrix Metalloproteinase-9 (MMP-9) induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in inflammatory bowel disease (IBD)
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 myosin light chain kinase (MLCK)
Summary
The intestinal epithelium is a single layer of cells within the gut lumen that serves an important protective function. Previous studies have shown that in animal models of colitis, MMP-9 was upregulated and played an important role in the development of intestinal inflammation [16,17,18,19]. Little is known about the mechanisms of MMP-9 induced increase in intestinal TJ permeability, and even less has been reported on whether MMP-9 has a critical role in the pathogenesis of IBD in relation to the TJ barrier function. The purpose of this study was to further elucidate the intracellular mechanisms involved in the MMP-9 induced increase in intestinal epithelial TJ permeability, using a well-established in vitro intestinal epithelial model system consisting of filter-grown Caco-2 monolayers. Matrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). The intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear
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