Regulation of Matrix Metalloproteinase (MMP) and Tissue Inhibitor of Matrix Metalloproteinase (TIMP) Genes During JHMV Infection of the Central Nervous System

  • Jiehao Zhou
  • Stephen A. Stohlman
  • Norman W. Marten
  • David R. Hinton
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 494)


The central nervous system (CNS) is refractive to many aspects of the immune system primarily due to its limited ability to repair damage induced by the cytopathic mechanisms deployed by most immune cells. A primary obstacle to CNS inflammation is the blood-brain-barrier (BBB), which limits entry of immune cells into the CNS. To pass the BBB, inflammatory cells release matrix metalloproteinases (MMPs); a growing family of proteases with overlapping substrate specificities for components of the extracellular matrix (reveiwed by Kieseier et al. 1999). MMPs break down the extracellular matrix surrounding the endothelial layer of BBB thereby permitting peripheral immune cells to traverse the BBB and migrate through the parenchyma of the CNS in response to inflammatory signals. To limit potential damage resulting from infiltration of inflammatory cells, MMP activity is tightly regulated at both the level of gene expression and proenzyme activation as well as by expression of a second gene family, the tissue inhibitors of MMPs (TIMPs). TIMPs act as competitive inhibitors for the active sites of MMPs and thus limit inflammatory infiltrates.


RNAse Protection Assay Mononuclear Cell Infiltration Immune Cell Infiltration naIve Mouse Mouse Hepatitis Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Esparza, J., C. Vilardell, J. Calvo, M. Juan, J. Vives, A. Urbano-Marquez, J. Yague and M. C. Cid. Fibronectin upregulates gelatinase B (MMP-9) and induces coordinate expression of gelatinase A (MMP-2) and its activator MTl-MMP (MMP-14) by human T lymphocyte cell lines. A process repressed through RAS/MAP kinase signalling pathways. Blood. 1999. 94:2754–2766PubMedGoogle Scholar
  2. Faris B., P. Mozzicato, R. Ferrera, M. Glembourtt, P. Toselli and C. Franzblau. Collagen of Brain Microvessel Preparations. Mircovasc. Res. 1982. 23:171–179CrossRefGoogle Scholar
  3. Fleming, J. O., M. Trousdale, F. E. Zactarim, S. A. Stohlman and L. P. Weiner. Pathogenicity of antigenic variants of murine Coronavirus JHM selected with mAb. J. Virol. 1986. 58:869–875.PubMedGoogle Scholar
  4. Giraudon, P., R. Szymocha, S. Buart, A. Bernard, L. Cartier, M. F. Belin and H. Akaoka. T lymphocytes activated by persistent viral infection differentially modify the expression of metalloproteinases and their endogenous inhibitors, TIMPs, in human astrocytes: relevance to HTLV-I-induced neurological disease. J. Immunol. 2000. 164:2718–2727.PubMedGoogle Scholar
  5. Goetzl EJ. Banda MJ. Leppert D. Matrix metalloproteinases in immunity. J. Immunol. 1996. 156:1–4.PubMedGoogle Scholar
  6. Gomis-Ruth, F.-X., K. Maskos, M. Betz, A. Bergner, R. Huber, K. Suszuki, N. Yoshida, H. Nagase, K. Brew, G. P. Bourenkov, H. Bartunik and W. Bode. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature. 1997. 389:77–81.PubMedCrossRefGoogle Scholar
  7. Kieseier, B. C., T. Seifert, G. Giovannoni and H. P. Hartung. Matrix metalloproteinases in inflammatory demyelination: targets for treatment. Neurology. 1999. 53:20–25.PubMedCrossRefGoogle Scholar
  8. Maeda, A. and R. A. Sobel. Matrix metalloproteinases in the normal human central nervous system, microglial nodules and multiple sclerosis lesions. J. Neuropath. Exp. Neuro. 1996. 55:300–309.CrossRefGoogle Scholar
  9. Ozenci V., L. Rinaldi, N. Teleshova, D. Matusevicius, P. Kivisakk, M. Kouwenhoven and H. Link. Metalloproteinases and their tissue inhibitors in multiple sclerosis. J. Autoimmun. 1999. 12:297–303.PubMedCrossRefGoogle Scholar
  10. Pagenstecher, A., A. K. Stalder and I. L. Campbell. RNAse protection assays for the simultaneous and semiquantitative analysis of multiple murine matrix metalloproteinase (MMP) and MMP inhibitor mRNAs. J. Immunol. Meth. 1997. 206:1–9.CrossRefGoogle Scholar
  11. Pagenstecher, A., A. K. Stalder, C. L. Kincaid, S. D. Shapiro, I. L. Campbell. Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states. Am. J. Path. 1998. 152:729–741.PubMedGoogle Scholar
  12. Shapiro, S. D. Diverse roles of macrophage matrix metalloproteinases in tissue destruction and tumor growth. Thromb & Haemo. 1999. 82:846–849.Google Scholar
  13. Williamson, J. S. P., K. Sykes and S. A. Stohlman. Characterization of brain infiltrating mononuclear cells during infection with mouse hepatitis virus strain JHM. J. Neuroimmunol. 1991. 32:199–207.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Jiehao Zhou
    • 1
  • Stephen A. Stohlman
    • 2
    • 3
  • Norman W. Marten
    • 1
  • David R. Hinton
    • 1
  1. 1.Department of PathologyUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Department of NeurologyUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Molecular Microbiology and Immunology Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

Personalised recommendations