{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T04:23:27Z","timestamp":1773203007044,"version":"3.50.1"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2010,6,1]],"date-time":"2010-06-01T00:00:00Z","timestamp":1275350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Inflammatory tissue destruction is central to pathology in CNS tuberculosis (TB). We hypothesized that microglial-derived matrix metalloproteinases (MMPs) have a key role in driving such damage. Analysis of all of the MMPs demonstrated that conditioned medium from Mycobacterium tuberculosis-infected human monocytes (CoMTb) stimulated greater MMP-1, -3, and -9 gene expression in human microglial cells than direct infection. In patients with CNS TB, MMP-1\/-3 immunoreactivity was demonstrated in the center of brain granulomas. Concurrently, CoMTb decreased expression of the inhibitors, tissue inhibitor of metalloproteinase-2, -3, and -4. MMP-1\/-3 secretion was significantly inhibited by dexamethasone, which reduces mortality in CNS TB. Surface-enhanced laser desorption ionization time-of-flight analysis of CoMTb showed that TNF-\u03b1 and IL-1\u03b2 are necessary but not sufficient for upregulating MMP-1 secretion and act synergistically to drive MMP-3 secretion. Chemical inhibition and promoter-reporter analyses showed that NF-\u03baB and AP-1 c-Jun\/FosB heterodimers regulate CoMTb-induced MMP-1\/-3 secretion. Furthermore, NF-\u03baB p65 and AP-1 c-Jun subunits were upregulated in biopsy granulomas from patients with cerebral TB. In summary, functionally unopposed, network-dependent microglial MMP-1\/-3 gene expression and secretion regulated by NF-\u03baB and AP-1 subunits were demonstrated in vitro and, for the first time, in CNS TB patients. Dexamethasone suppression of MMP-1\/-3 gene expression provides a novel mechanism explaining the benefit of steroid therapy in these patients.<\/jats:p>","DOI":"10.4049\/jimmunol.0903811","type":"journal-article","created":{"date-parts":[[2010,5,5]],"date-time":"2010-05-05T22:53:56Z","timestamp":1273100036000},"page":"6492-6503","source":"Crossref","is-referenced-by-count":68,"title":["<i>Mycobacterium tuberculosis<\/i>\n                    Upregulates Microglial Matrix Metalloproteinase-1 and -3 Expression and Secretion via NF-\u03baB\u2013 and Activator Protein-1\u2013Dependent Monocyte Networks"],"prefix":"10.1093","volume":"184","author":[{"given":"Justin A","family":"Green","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul T","family":"Elkington","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline J","family":"Pennington","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of East Anglia , Norwich,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Roncaroli","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Charing Cross Campus, Imperial College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shruti","family":"Dholakia","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel C","family":"Moores","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anwen","family":"Bullen","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna C","family":"Porter","sequence":"additional","affiliation":[{"name":"Medical Research Council Laboratory of Molecular Cell Biology, University College London , London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Agranoff","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dylan R","family":"Edwards","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of East Anglia , Norwich,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon S","family":"Friedland","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2010,6,1]]},"reference":[{"key":"2026012806344956700_r1","doi-asserted-by":"crossref","first-page":"e1772","DOI":"10.1371\/journal.pone.0001772","article-title":"Clinical and microbiological features of HIV-associated tuberculous meningitis in Vietnamese adults.","volume":"3","author":"Torok","year":"2008","journal-title":"PLoS One"},{"key":"2026012806344956700_r2","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.4049\/jimmunol.176.3.2007","article-title":"Pretreatment intracerebral and peripheral blood immune responses in Vietnamese adults with tuberculous meningitis: diagnostic value and relationship to disease severity and outcome.","volume":"176","author":"Simmons","year":"2006","journal-title":"J. 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