Archives of Pharmacal Research

, Volume 28, Issue 11, pp 1257–1262 | Cite as

MAP Kinase activation is required for the MMP-9 induction by TNF-stimulation



MMP-9 is a metalloproteinase capable of basement membrane degradationin vivo. Expression of MMP-9 can be found in normal conditions such as trophoblasts, osteoclasts, and leukocytes and their precursors. They also occur as well as in pathological conditions, such as the invasive growth of primary tumors, metastasis, angiogenesis, rheumatoid arthritis, and periodontal diseases. MMP-9 upregulation can be highly induced by a wide range of agents. These agents include growth factors, cytokines, cell-cell, and cell-ECM adhesion molecules, and agents altering cell shape. Here, we observed that TNF-α stimulated human monocytic cell line, HL-60 produced MMP-9 in a dose and time dependent manner. Real time PCR results indicated transcriptional upregulation of MMP-9 as early as 3 h post TNF-α stimulation. To investigate the signaling pathway underlined in TNF-α induced MMP-9 expression, three MAP kinase inhibitors were added to cells 1 h prior to TNF-α treatment. The ERK inhibitor completely abolished MMP-9 expression by TNF-α. But neither p38 MAP kinase nor JNK inhibitor had an effect on TNF-α induced MMP-9 expression, suggesting that ERK activation is required for the MMP-9 induction by TNF-α. Taken together, we found that TNF-α stimulation facilitates ERK activation, which results in the transcriptional upregulation of MMP-9 gene and subsequent MMP-9 production and secretion.

Key words

TNF-α MMP-9 MAP Kinase Signaling pathway 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bazzoni, F. and Beutler, B., The tumor necrosis factor ligand and receptor families.N. Engl. J. Med., 334, 1717–1725 (1996).PubMedCrossRefGoogle Scholar
  2. Borregaard, N., Sehested, M., Nielsen, B. S., Sengelov, H. and Kjeldsen, L., Biosynthesis of granule proteins in normal human bone marrow cells. Gelatinase is a marker of terminal neutrophil differentiation.Blood, 85, 812–817 (1995).PubMedGoogle Scholar
  3. Carswell, E. A., Old, L. J., Kassel, R. L, Green, S., Fiore, N. and Williamson, B., An endotoxin-induced serum factor that causes necrosis of tumors.Proc. Natl. Acad. Sci. U.S.A., 72, 3666–3670 (1975).PubMedCrossRefGoogle Scholar
  4. Damsky, C. H. and Werb, Z., Signal transduction by integrin receptors for extracellular matrix: cooperative processing of extracellular information.Curr. Opin. Cell Biol., 4, 772–781 (1992).PubMedCrossRefGoogle Scholar
  5. Dong, Z., Nemeth, J. A., Cher, M. L., Palmer, K. C., Bright, R. C., and Fridman, R., Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cells.Int. J. Cancer, 93, 507–515 (2001).PubMedCrossRefGoogle Scholar
  6. Drynda, A., Quax, P. H., Neumann, M., van der Laan, W. H., Pap, G., Drynda, S., Meinecke, I., Kekow, J., Neumann, W., Huizinga, T. W., Naumann, M., Konig, W., and Pap, T., Gene transfer of tissue inhibitor of metalloproteinases-3 reverses the inhibitory effects of TNF-alpha on Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts.J. Immunol., 174, 6524–6531 (2005).PubMedGoogle Scholar
  7. Hanemaaijer, R., Sorsa, T., Konttinen, Y. T., Ding, Y., Sutinen, M., Visser, H., van Hinsbergh, V. W., Helaakoski, T., Kainulainen, T., Ronka, H., Tschesche, H., and Salo, T., Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells. Regulation by tumor necrosis factor-alpha and doxycycline.J. Biol. Chem., 272, 31504–31509 (1997).PubMedCrossRefGoogle Scholar
  8. Harvey, M., Leco, K. J., Arcellana-Panlilio, M. Y., Zhang, X., Edwards, D. R., and Schultz, G. A., Proteinase expression in early mouse embryos is regulated by leukaemia inhibitory factor and epidermal growth factor.Development, 121, 1005–1014 (1995).PubMedGoogle Scholar
  9. Ho, L. J., Lin, L. C., Hung, L. F., Wang, S. J., Lee, H., Chang, D. M., Lai, J. H., and Tai, T. Y., Retinoic acid blocks proinflammatory cytokine-induced matrix metalloproteinase production by down-regulating JNK-AP-1 signaling in human chondrocytes.Biochem. Pharmacol., 70, 200–208 (2005).PubMedCrossRefGoogle Scholar
  10. Ishikawa, T., Nishigaki, F., Miyata, S., Hirayama, Y., Minoura, K., Imanishi, J., Neya, M., Mizutani, T., Imamura, Y., Ohkubo, Y., and Mutoh, S., Prevention of progressive joint destruction in adjuvant induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR217840.Eur. J. Pharmacol., 508, 239–247 (2005).PubMedCrossRefGoogle Scholar
  11. Kassiri, Z., Oudit, G. Y., Sanchez, O., Dawood, F., Mohammed, F. F., Nuttall, R. K., Edwards, D. R., Liu, P. P., Backx, P. H., and Khokha, R., Combination of tumor necrosis factor-alpha ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice.Circ. Res., 97, 380–390 (2005).PubMedCrossRefGoogle Scholar
  12. Kim, W. J., Kang, Y. J., Koh, E. M., Ahn, K. S., Cha, H. S., and Lee, W. H., LIGHT is involved in the pathogenesis of rheumatoid arthritis by inducing the expression of proinflammatory cytokines and MMP-9 in macrophages.Immunology, 114, 272–279 (2005).PubMedCrossRefGoogle Scholar
  13. Konradsson, K., and van Dijken, J. W., Interleukin-1 levels in gingival crevicular fluid adjacent to restorations of calcium aluminate cement and resin composite.J. Clin. Periodontal., 32, 462–466 (2005).CrossRefGoogle Scholar
  14. Martin, J., Eynstone, L., Davies, M., and Steadman, R., Induction of metalloproteinases by glomerular mesangial cells stimulated by proteins of the extracellular matrix.J. Am. Soc. Nephrol., 12, 88–96 (2001).PubMedGoogle Scholar
  15. Massova, I., Kotra, L. P., Fridman, R., and Mobashery, S., Matrix metalloproteinases: structures, evolution, and diversification.FASEB. J., 12, 1075–1095 (1998).PubMedGoogle Scholar
  16. Migita, K., Eguchi, K., Kawabe, Y., Ichinose, Y., Tsukada, T., Aoyagi, T., Nakamura, H., and Nagataki, S., TNF-alpha-mediated expression of membrane-type matrix metallo-proteinase in rheumatoid synovial fibroblasts.Immunology, 89, 553–557 (1996).PubMedCrossRefGoogle Scholar
  17. Overall, M., Sodek, J., McCulloch, C. A., and Birek, P., Evidence for polymorphonuclear leukocyte collagenase and 92-kilodalton gelatinase in gingival crevicular fluid.Infect. Immun., 59, 4687–4692 (1991).PubMedGoogle Scholar
  18. Reichardt, L. F. and Tomaselli, K. J., Extracellular matrix molecules and their receptors: functions in neural development.Annu. Rev. Neurosci., 14, 531–570 (1991).PubMedCrossRefGoogle Scholar
  19. Shapira, J., Berenstein-Ajzman, G., Engelhard, D., Cahan, S., Kalickman, I., and Barak, V., Cytokine levels in gingival crevicular fluid of erupting primary teeth correlated with systemic disturbances accompanying teething.Pediatr. Dent, 25, 441–448 (2003).PubMedGoogle Scholar
  20. Suffys, P., Beyaert, R., Van Roy, F., and Fiers, W., TNF in combination with interferon-gamma is cytotoxic to normal, untransformed mouse and rat embryo fibroblast-like cells.Anticancer Res., 9, 167–171 (1989).PubMedGoogle Scholar
  21. Tanimura, Y., Kokuryo, T., Tsunoda, N., Yamazaki, Y., Oda, K., Nimura, Y., Naing Mon N., Huang, P., Nakanuma, Y., Chen, M. F., Jan, Y. Y., Yeh, T. S., Chiu, C. T., Hsieh, L. L., and Hamaguchi, M., Tumor necrosis factor alpha promotes invasiveness of cholangiocarcinoma cellsvia its receptor, TNFR2.Cancer Lett., 219, 205–213 (2005).PubMedCrossRefGoogle Scholar
  22. Tervahartiala, T., Pirila, E., Ceponis, A., Maisi, P., Salo, T., Tuter, G., Kallio, P., Tornwall, J., Srinivas, R., Konttinen, Y. T., and Sorsa, T., Thein vivo expression of the collagenolytic matrix metalloproteinases (MMP-2, -8, -13, and -14) and matrilysin (MMP-7) in adult and localized juvenile periodontitis.J. Dent. Res., 79, 1969–1977 (2000).PubMedCrossRefGoogle Scholar
  23. Wang, X., Liang, J., Koike, T., Sun, H., Ichikawa, T., Kitajima, S., Morimoto, M., Shikama, H., Watanabe, T., Sasaguri, Y, and Fan, J., Overexpression of human matrix metalloproteinase-12 enhances the development of inflammatory arthritis in transgenic rabbits.Am. J. Pathol., 165, 1375–1383 (2004).PubMedGoogle Scholar
  24. Wei, P. F., Ho, K. Y., Ho, Y. P., Wu, Y. M., Yang, Y. H, and Tsai, C. C., The investigation of glutathione peroxidase, lactoferrin, myeloperoxidase and interleukin-1beta in gingival crevicular fluid: implications for oxidative stress in human periodontal diseases.J. Periodontal. Res., 39, 287–293 (2004).PubMedCrossRefGoogle Scholar
  25. Witty, J. P., Foster, S.A., Stricklin, G. P., Matrisian, L. M., and Stern, P. H., Parathyroid hormone-induced resorption in fetal rat limb bones is associated with production of the metalloproteinases collagenase and gelatinase B.J. Bone Miner. Res., 11, 72–78 (1996).PubMedCrossRefGoogle Scholar
  26. Woessner, J. F., Jr., Matrix metalloproteinase inhibition. From the Jurassic to the third millennium.Ann. N. Y. Acad. Sci., 878, 388–403 (1999).PubMedCrossRefGoogle Scholar
  27. Woessner, J. F., Jr. and Gunja-Smith, Z., Role of metalloproteinases in human osteoarthritis.J. Rheumatol. Suppl., 27, 99–101 (1991).PubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2005

Authors and Affiliations

  1. 1.Department of Pulmonary, School of MedicineCatholic University of DaeguDaeguKorea
  2. 2.Aging-associated Vascular Disease Research Center, College of MedicineYeungnam UniversityDaeguKorea

Personalised recommendations