Regulation of matrilysin expression in airway epithelial cells by Pseudomonas aeruginosa flagellin

Matrilysin (matrix metalloproteinase-7) is expressed by mucosal epithelia t hroughout the body and functions in host defense by activating murine intes tinal a-defensins. In normal adult human lung, matrilysin is expressed at l ow 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 epit helial cells. Indeed, acute infection with Pseudomonas aeruginosa (but not Staphylococcus aureus, Haemophilus influenzae, or Klebsiella pneumoniae) in duced the expression of matrilysin in Calu-3 lung epithelial cells. Increas ed 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 an d laboratory strains induced matrilysin expression to similar levels. Flage llin, the monomeric precursor of bacterial flagella, was identified as the inductive factor released by P. aeruginosa that regulated matrilysin expres sion. In addition, flagellin-null mutants failed to stimulate matrilysin ex pression in cultured cells or in lungs infected in vivo. These data show th at P. aeruginosa (and specifically flagellin) potently stimulates matrilysi n expression in lung epithelial cells and may mediate the overexpression of this proteinase in CF lungs.