Matrix Metalloproteinase 9-induced Increase in Intestinal Epithelial Tight Junction Permeability Contributes to the Severity of Experimental DSS Colitis

Am J Physiol Gastrointest Liver Physiol. 2015 Dec 15;309(12):G988-97. doi: 10.1152/ajpgi.00256.2015. Epub 2015 Oct 29.

Abstract

Recent studies have implicated a pathogenic role for matrix metalloproteinases 9 (MMP-9) in inflammatory bowel disease. Although loss of epithelial barrier function has been shown to be a key pathogenic factor for the development of intestinal inflammation, the role of MMP-9 in intestinal barrier function remains unclear. The aim of this study was to investigate the role of MMP-9 in intestinal barrier function and intestinal inflammation. Wild-type (WT) and MMP-9(-/-) mice were subjected to experimental dextran sodium sulfate (DSS) colitis by administration of 3% DSS in drinking water for 7 days. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon using fluorescently labeled dextran. The DSS-induced increase in the colonic permeability was accompanied by an increase in intestinal epithelial cell MMP-9 expression in WT mice. The DSS-induced increase in intestinal permeability and the severity of DSS colitis was found to be attenuated in MMP-9(-/-) mice. The colonic protein expression of myosin light chain kinase (MLCK) and phospho-MLC was found to be significantly increased after DSS administration in WT mice but not in MMP-9(-/-) mice. The DSS-induced increase in colonic permeability and colonic inflammation was attenuated in MLCK(-/-) mice and MLCK inhibitor ML-7-treated WT mice. The DSS-induced increase in colonic surface epithelial cell MLCK mRNA was abolished in MMP-9(-/-) mice. Lastly, increased MMP-9 protein expression was detected within the colonic surface epithelial cells in ulcerative colitis cases. These data suggest a role of MMP-9 in modulation of colonic epithelial permeability and inflammation via MLCK.

Keywords: matrix metalloproteinase; myosin light chain kinase; tight junction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Colitis / chemically induced
  • Colitis / enzymology*
  • Colitis / genetics
  • Colitis / pathology
  • Colitis / prevention & control
  • Colon / drug effects
  • Colon / enzymology*
  • Colon / pathology
  • Dextran Sulfate*
  • Disease Models, Animal
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / enzymology*
  • Intestinal Mucosa / pathology
  • Matrix Metalloproteinase 9 / analysis
  • Matrix Metalloproteinase 9 / deficiency
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myosin Light Chains / metabolism
  • Myosin-Light-Chain Kinase / antagonists & inhibitors
  • Myosin-Light-Chain Kinase / genetics
  • Myosin-Light-Chain Kinase / metabolism
  • Permeability
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Severity of Illness Index
  • Signal Transduction
  • Tight Junction Proteins / metabolism
  • Tight Junctions / drug effects
  • Tight Junctions / enzymology*
  • Tight Junctions / pathology
  • Time Factors

Substances

  • Myosin Light Chains
  • Protein Kinase Inhibitors
  • Tight Junction Proteins
  • Dextran Sulfate
  • Myosin-Light-Chain Kinase
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse