Synergistic up-regulation of epithelial cell matrix metalloproteinase-9 secretion in tuberculosis

Am J Respir Cell Mol Biol. 2007 Oct;37(4):431-7. doi: 10.1165/rcmb.2007-0011OC. Epub 2007 Jun 15.


Mycobacterium tuberculosis (MTb) kills approximately 2 million people each year. MTb must drive host tissue destruction to disseminate and also to cause pulmonary cavitation. Matrix metalloproteinase-9 (MMP-9, gelatinase B) is implicated in this Tb-related immunopathology. We demonstrate that conditioned media from MTb-infected monocytes (CoMTb), but not direct infection with MTb, up-regulates MMP-9 gene expression and secretion from primary human bronchial epithelial cells (NHBE). MMP-9 secretion was increased 8.7-fold by CoMTb (P < 0.05) as assayed by gelatin zymography. A549 and 16HBE14o epithelial cell MMP secretion was significantly less than primary NHBE secretion. MMP-9 secretion was decreased 53.2% by inhibition of the p38 mitogen-activated protein kinase (MAPK) by SB203580 (P < 0.01) and 48.3% by inhibition of extracellular signal-regulated kinase with PD98059 (P < 0.05). MMP-9 secretion was prostaglandin independent. TNF-alpha was necessary but not sufficient for MMP-9 up-regulation by the monocyte-epithelial cell network. Soluble factors derived from Tb culture synergized with TNF-alpha to increase MMP-9 secretion by NHBE 6-fold (P < 0.01 compared with either stimulus alone). Together, these data reveal a new mechanism by which host- and pathogen-derived factors act together in MTb infection to drive MAPK-dependent MMP-9 secretion from respiratory epithelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology*
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Interleukin-1beta / pharmacology
  • Interleukin-6 / pharmacology
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Monocytes / drug effects
  • Monocytes / enzymology
  • Monocytes / microbiology
  • Mycobacterium tuberculosis / physiology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / enzymology
  • Respiratory Mucosa / microbiology
  • Tuberculosis / enzymology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Bacterial Proteins
  • Interleukin-1beta
  • Interleukin-6
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 9