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Monocyte-astrocyte networks regulate matrix metalloproteinase gene expression and secretion in central nervous system tuberculosis in vitro and in vivo.

Harris, James E., Nuttall, Robert K., Elkington, Paul T., Green, Justin A., Horncastle, Donna E., Graeber, Manuel B., Edwards, Dylan R. and Friedland, Jon S. (2007) Monocyte-astrocyte networks regulate matrix metalloproteinase gene expression and secretion in central nervous system tuberculosis in vitro and in vivo. Journal of Immunology, 178, (2), pp. 1199-1207. (PMID:17202385).

Record type: Article


CNS tuberculosis (CNS-TB) is the most deadly form of tuberculous disease accounting for 10% of clinical cases. CNS-TB is characterized by extensive tissue destruction, in which matrix metalloproteinases (MMPs) may play a critical role. We investigated the hypothesis that Mycobacterium tuberculosis activates monocyte-astrocyte networks increasing the activity of key MMPs. We examined the expression of all human MMPs and the tissue inhibitors of metalloproteinases (TIMPs) in human astrocytes stimulated by conditioned medium from M. tuberculosis-infected monocytes (CoMTB). Real-time RT-PCR showed that gene expression of MMP-1, -2, -3, -7, and -9 was increased (p < 0.05). MMP-9 secretion was significantly up-regulated at 24 h and increased over 120 h (p < 0.01). MMP-1, -3, and -7 secretion was not detected. Secretion of MMP-2 was constitutive and unaffected by CoMTB. Astrocyte gene expression and secretion of TIMP-1 was not affected by CoMTB although TIMP-2 secretion increased 3-fold at 120 h. Immunohistochemical analysis of human brain biopsies confirmed that astrocyte MMP-9 secretion is a predominant feature in CNS-TB in vivo. Dexamethasone inhibited astrocyte MMP-9, but not TIMP-1/2 secretion in response to CoMTB. CoMTB stimulated the nuclear translocation of NF-kappaB, inducing a 6-fold increase in nuclear p65 and a 2-fold increase in nuclear p50. This was associated with degradation of IkappaBalpha and beta within 30 min, persisting for 24 h. In summary, networks active between monocytes and astrocytes regulate MMP-9 activity in tuberculosis and astrocytes are a major source of MMP-9 in CNS-TB. Astrocytes may contribute to a matrix degrading environment within the CNS and subsequent morbidity and mortality.

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Published date: 15 January 2007
Organisations: Faculty of Medicine


Local EPrints ID: 341062
ISSN: 0022-1767
PURE UUID: 0214c55e-4d60-4cbd-b716-8c550e61b252
ORCID for Paul T. Elkington: ORCID iD

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Date deposited: 12 Jul 2012 10:33
Last modified: 18 Jul 2017 05:39

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Author: James E. Harris
Author: Robert K. Nuttall
Author: Justin A. Green
Author: Donna E. Horncastle
Author: Manuel B. Graeber
Author: Dylan R. Edwards
Author: Jon S. Friedland

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