Protein tyrosine kinase and p38 MAP kinase pathways are involved in stimulation of matrix metalloproteinase-9 by TNF-alpha in human monocytes

Immunol Lett. 2006 Jul 15;106(1):34-41. doi: 10.1016/j.imlet.2006.04.003. Epub 2006 May 4.


Matrix metalloproteinase-9 (MMP-9), through its catalytic and non-catalytic activities, plays critical roles in inflammation, tumor invasion and angiogenesis. Human monocytes actively involved in inflammatory and tumoral states secrete proMMP-9 (92kDa). Endogenous TNF-alpha stimulates MMP-9 gene transcription in monocytes through NF-kappaB activation. In this study, we investigated the intracellular signaling pathways underlying TNF-alpha/NF-kappaB-dependent expression of MMP-9 in monocytes using chemical inhibitors that specifically inhibit distinct kinase pathways. We confirmed the expression of MMP-9 by reverse transcription chain reaction (RT-PCR), ELISA and gelatin zymography. PGE2/cAMP inhibitor indomethacin, PI-3K inhibitor wortmannin, PKC inhibitor bisindolylmaleimide and PKA inhibitor H-89 did not affect the levels of released MMP-9. In contrast, MMP-9 mRNA and protein expression was down-regulated by p38 MAPK inhibitor SB203580 and protein tyrosine kinase (PTK) inhibitor tyrphostin 25. These inhibitors increased IkappaB-alpha levels, which correlate with decreased NF-kappaB activation. Although SB203580 induced a decrease in TNF-alpha release, addition of exogenous TNF-alpha did not reverse the inhibitory effect of SB203580 toward MMP-9 thus suggesting that SB203580 could modulate down-stream effects of TNF-alpha. In parallel, TIMP-1 levels decreased in the presence of SB203580. Both kinase inhibitors did not influence the maturation pathway of monocytes. Our results indicate that these two inhibitors of p38 MAPK and PTK pathways could be used as combined targets for inhibiting MMP-9 expression in inflamed tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Adhesion / drug effects
  • Cell Differentiation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Humans
  • I-kappa B Kinase / metabolism
  • Imidazoles / pharmacology
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Middle Aged
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / enzymology*
  • Monocytes / metabolism
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational
  • Protein-Tyrosine Kinases / metabolism*
  • Pyridines / pharmacology
  • Signal Transduction* / drug effects
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tyrphostins / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridines
  • Tissue Inhibitor of Metalloproteinase-1
  • Tumor Necrosis Factor-alpha
  • Tyrphostins
  • tyrphostin 25
  • Protein-Tyrosine Kinases
  • I-kappa B Kinase
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 9
  • SB 203580