Abstract
Matrilysin (matrix metalloproteinase-7) is expressed by mucosal epithelia throughout the body and functions in host defense by activating murine intestinal alpha-defensins. In normal adult human lung, matrilysin is expressed at low levels in the airway epithelium, but is markedly up-regulated in cystic fibrosis (CF). Because CF lungs support a heavy bacterial load, we assessed if relevant CF pathogens regulate matrilysin expression in human lung epithelial cells. Indeed, acute infection with Pseudomonas aeruginosa (but not Staphylococcus aureus, Haemophilus influenzae, or Klebsiella pneumoniae) induced the expression of matrilysin in Calu-3 lung epithelial cells. Increased matrilysin mRNA levels were detectable at 3 h post-infection and peaked at a 25-fold induction between 6 and 8 h. Both P. aeruginosa CF isolates and laboratory strains induced matrilysin expression to similar levels. Flagellin, the monomeric precursor of bacterial flagella, was identified as the inductive factor released by P. aeruginosa that regulated matrilysin expression. In addition, flagellin-null mutants failed to stimulate matrilysin expression in cultured cells or in lungs infected in vivo. These data show that P. aeruginosa (and specifically flagellin) potently stimulates matrilysin expression in lung epithelial cells and may mediate the overexpression of this proteinase in CF lungs.
Highlights
Tured cells or in lungs infected in vivo
A moderate to intense signal for matrilysin mRNA colocalized with cells that had strong staining for the protein (Fig. 1, E and F, G and H), indicating that this MMP was actively expressed in the airway epithelia of cystic fibrosis (CF) lungs
We have demonstrated that matrilysin is prominently and invariantly expressed in the airway and respiratory epithelia of lungs from patients with CF and that exposure of lung epithelial cells to P. aeruginosa, a relevant CF pathogen, markedly stimulates the expression of this MMP
Summary
Tured cells or in lungs infected in vivo. These data show Unlike many MMPs, which are typically expressed or rethat P. aeruginosa (and flagellin) potently leased in response to injury, disease, or inflammation, matristimulates matrilysin expression in lung epithelial cells lysin is expressed by non-injured, non-inflamed exocrine and and may mediate the overexpression of this proteinase mucosal epithelia in most adult human tissues. Acute infection with Pseudomonas aeruginosa (but not Staphylococcus aureus, Haemophilus influenzae, or Klebsiella pneumoniae) induced the expression of matrilysin in Calu-3 lung epithelial cells. A number of bacterial gene products stimulate pro-inflammatory responses in epithelial cells, and we identified P. aeruginosa flagellin, the monomeric component of flagella, as the factor controlling matrilysin expression.
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