DOI QR코드

DOI QR Code

Comparison of the Effects of Matrix Metalloproteinase Inhibitors on TNF-α Release from Activated Microglia and TNF-α Converting Enzyme Activity

  • Lee, Eun-Jung (Department of Molecular Medicine, Tissue Injury Defense Research Center, Ewha Womans University Medical School) ;
  • Moon, Pyong-Gon (Department of Molecular Medicine, Kyongbuk National University) ;
  • Baek, Moon-Chang (Department of Molecular Medicine, Kyongbuk National University) ;
  • Kim, Hee-Sun (Department of Molecular Medicine, Tissue Injury Defense Research Center, Ewha Womans University Medical School)
  • Received : 2014.09.03
  • Accepted : 2014.09.19
  • Published : 2014.09.30

Abstract

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix composition and are also involved in processing various bioactive molecules such as cell-surface receptors, chemokines, and cytokines. Our group recently reported that MMP-3, -8, and -9 are upregulated during microglial activation and play a role as proinflammatory mediators (Lee et al., 2010, 2014). In particular, we demonstrated that MMP-8 has tumor necrosis factor alpha (TNF-${\alpha}$)-converting enzyme (TACE) activity by cleaving the prodomain of TNF-${\alpha}$ and that inhibition of MMP-8 inhibits TACE activity. The present study was undertaken to compare the effect of MMP-8 inhibitor (M8I) with those of inhibitors of other MMPs, such as MMP-3 (NNGH) or MMP-9 (M9I), in their regulation of TNF-${\alpha}$ activity. We found that the MMP inhibitors suppressed TNF-${\alpha}$ secretion from lipopolysaccharide (LPS)-stimulated BV2 microglial cells in an order of efficacy: M8I>NNGH>M9I. In addition, MMP inhibitors suppressed the activity of recombinant TACE protein in the same efficacy order as that of TNF-${\alpha}$ inhibition (M8I>NNGH>M9I), proving a direct correlation between TACE activity and TNF-${\alpha}$ secretion. A subsequent pro-TNF-${\alpha}$ cleavage assay revealed that both MMP-3 and MMP-9 cleave a prodomain of TNF-${\alpha}$, suggesting that MMP-3 and MMP-9 also have TACE activity. However, the number and position of cleavage sites varied between MMP-3, -8, and -9. Collectively, the concurrent inhibition of MMP and TACE by NNGH, M8I, or M9I may contribute to their strong anti-inflammatory and neuroprotective effects.

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

References

  1. Verma, R. P. and Hansch, C. (2007) Matrix metalloproteinases (MMPs): Chemical-biological functions and (Q)SARs. Bioorg. Med. Chem. 15, 2223-2268 https://doi.org/10.1016/j.bmc.2007.01.011
  2. Verslegers, M., Lemmens, K., Hove, I. V. and Moons, L. (2013) Matrix metalloproteinase-2 and-9 as promising benefactors in development, plasticity and repair of the nervous system. Prog. Neurobiol. 105, 60-78. https://doi.org/10.1016/j.pneurobio.2013.03.004
  3. Woo, M. S., Park, J. S., Choi, I. Y., Kim, W. K. and Kim, H. S. (2008) Inhibition of MMP-3 or-9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and iNOS in microglia. J. Neurochem 106, 770-780. https://doi.org/10.1111/j.1471-4159.2008.05430.x
  4. Aggarwal, B. B. (2003) Signaling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol. 3, 745-756. https://doi.org/10.1038/nri1184
  5. Agrawal, S. M., Lau, L. and Yong V. W. (2008) MMPs in the central nervous system: where the good guys go bad. Semin. Cell Dev. Biol. 19, 42-51. https://doi.org/10.1016/j.semcdb.2007.06.003
  6. Asai, M., Hattori, C., Szabo, B., Sasagawa, N., Maruyama, K., Tanuma, S. and Ishiura, S. (2003) Putative function of ADAM9, ADAM10, and ADAM17 as APP ${\alpha}$-secretase. Biochem. Biophys. Res. Commun. 301, 231-235. https://doi.org/10.1016/S0006-291X(02)02999-6
  7. Bahia M. S. and Silakari O. (2010) Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders. Chem. Biol. Drug Des. 75, 415-443. https://doi.org/10.1111/j.1747-0285.2010.00950.x
  8. Black, R. A., Rauch, C. T., Kozlosky, C. J., Peschon, J. J., Slack, J. L., Wolfson, M. F., Castner, B. J., Stocking, K. L., Reddy, P., Srinivasan, S., Nelson, N., Boiani, N., Schooley, K. A., Gerhart M., Davis, R., Fitzner, J. N., Johnson, R. S., Paxton, R. J., March, C. J. and Cerretti, D. P. (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729-733. https://doi.org/10.1038/385729a0
  9. Bocchini, V., Mazzolla, R., Barluzzi, R., Blasi, E., Sick, P. and Kettenmann, H. (1992) An immortalized cell line expresses properties of activated microglial cells. J. Neurosci. Res. 31, 616-621. https://doi.org/10.1002/jnr.490310405
  10. Candelario-Jalil, E., Yang, Y. and Rosenberg, G. A. (2009) Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158, 983-994. https://doi.org/10.1016/j.neuroscience.2008.06.025
  11. Dev, R., Srivastava, P. K., Iyer, J. P., Dastidar, S. G. and Ray, A. (2010) Therapeutic potential of matrix metalloprotease inhibitors in neuropathic pain. Expert Opin. Investig. Drugs 19, 455-468. https://doi.org/10.1517/13543781003643486
  12. Gearing, A. J., Beckett, P., Christodoulou, M., Churchill, M., Clements, J.,M., Crimmin, M., Davidson, A. H., Drummond, A. H., Galloway, W. A., Gilbert, R., Gordon, J. L., Leber, T. M., Mangan, M., Miller, K., Nayee, P., Owen, K., Patel, S., Thomasv W., Wells, G., Wood, L. M. and Woolley, K. (1995) Matrix metalloproteinases and processing of pro-TNF-alpha. J. Leukoc. Biol. 57, 774-777. https://doi.org/10.1002/jlb.57.5.774
  13. Hu, J., Van den, Steen P. E., Sang, Q. X. A. and Opdenakker, G. (2007) Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat. Rev. Drug Dicsov. 6, 480-498. https://doi.org/10.1038/nrd2308
  14. Javaid, M. A., Abdallah, M. N., Ahmed, A. S. and Sheikh, Z. (2013) Matrix metalloproteinases and their pathological upregulation in multiple sclerosis: an overview. Acta Neurol. Belg. 113, 381-390. https://doi.org/10.1007/s13760-013-0239-x
  15. Kataoka, H. (2009) EGFR ligands and their signaling scissors, ADAMs, as new molecular targets for anticancer treatments. J. Dermatol. Sci. 56, 148-153. https://doi.org/10.1016/j.jdermsci.2009.10.002
  16. Lee, E. J., Woo, M. S., Moon, P. G., Baek, M. C., Choi, I. Y., Kim, W. K., Junn, E. and Kim, H. S. (2010) ${\alpha}$-Synuclein activates microglia by inducing the expressions of matrix metalloproteases and the subsequent activation of protease-activated receptor-1. J. Immunol. 185, 615-623. https://doi.org/10.4049/jimmunol.0903480
  17. Lee, E. J., Han, J. E., Woo, M. S., Shin, J. A., Park, E. M., Kang, J. L., Moon, P. G., Baek, M. C., Son, W. S., Ko, Y. T., Choi, J. W. and Kim, H. S. (2014) Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-${\alpha}$ activation. J. Immunol. 193, 2384-2393. https://doi.org/10.4049/jimmunol.1303240
  18. Li, N. G., Tang, Y. P., Duan, J. A. and Shi, Z. H. (2014) Matrix metalloproteinase inhibitors: a patent review (2011-2013). Expert Opin. Ther. Pat. 24, 1039-1052. https://doi.org/10.1517/13543776.2014.937424
  19. Mayhan, W. G. (2002) Cellular mechanisms by which tumor necrosis factor-a produces disruption of the blood-brain barrier. Brain Res. 927, 144-152. https://doi.org/10.1016/S0006-8993(01)03348-0
  20. McCoy, M. and Tansey, M. G. (2008) TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J. Neuroinflammation 5, 45. https://doi.org/10.1186/1742-2094-5-45
  21. Minond, D., Cudic, M., Bionda, N., Giulianotti, M., Maida, L., Houghten, R. A. and Fields, G. B. (2012) Discovery of novel inhibitors of a disintegrin and metalloprotease 17 (ADAM17) using glycosylated and non-glycosylated substrates. J. Biol. Chem. 287, 36473-36487. https://doi.org/10.1074/jbc.M112.389114
  22. Morancho, A., Rosell, A., Garcia-Bonilla L. and Montaner J. (2010) Matrix metalloproteinase and stroke infarct size: role for anti-inflammatory treatment. Ann. N. Y. Acad. Sci. 1207, 123-133. https://doi.org/10.1111/j.1749-6632.2010.05734.x
  23. Moss, M. L., Jin, S. L., Milla, M. E., Bickett, D. M., Burkhart, W., Carter, H. L., Chen, W. J., Clay, W. C., Didsbury, J. R., Hassler, D., Hoffman, C. R., Kost, T. A., Lambert, M. H., Leesnitzer, M. A., McCauley, P., McGeehan, G., Mitchell, J., Moyer, M., Pahel, G., Rocque, W., Overton, L. K., Schoenen, F., Seaton, T., Su, J. L. and Becherer, J. D. (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385, 733-736 https://doi.org/10.1038/385733a0
  24. Moss, M. L., Sklair-Tavron, L. and Nudelman, R. (2008) Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 4, 300-309.
  25. Rosenberg, G. A. (2009) Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 8, 205-216. https://doi.org/10.1016/S1474-4422(09)70016-X
  26. Tian, L., Ma, L., Kaarela, T. and Li, Z. (2012) Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases. J. Neuroinflammation 9, 155. https://doi.org/10.1186/1742-2094-9-155

Cited by

  1. Thioredoxin fusion construct enables high-yield production of soluble, active matrix metalloproteinase-8 (MMP-8) in Escherichia coli vol.122, 2016, https://doi.org/10.1016/j.pep.2016.02.012
  2. Complex Roles of Microglial Cells in Ischemic Stroke Pathobiology: New Insights and Future Directions vol.18, pp.3, 2017, https://doi.org/10.3390/ijms18030496
  3. Ethanol-Induced TLR4/NLRP3 Neuroinflammatory Response in Microglial Cells Promotes Leukocyte Infiltration Across the BBB vol.41, pp.1-2, 2016, https://doi.org/10.1007/s11064-015-1760-5
  4. Anti-Inflammatory and Antioxidant Mechanism of Tangeretin in Activated Microglia vol.11, pp.2, 2016, https://doi.org/10.1007/s11481-016-9657-x
  5. Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes vol.74, pp.12, 2017, https://doi.org/10.1007/s00018-017-2463-7