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IFNgamma synergizes with IL-1beta to up-regulate MMP-9 secretion in a cellular model of central nervous system tuberculosis.

Abstract
Matrix metalloproteinase-9 (MMP-9) activity is implicated in pathogenesis of central nervous system tuberculosis (CNS-TB). IFNgamma, a key cytokine in TB, usually inhibits MMP-9 secretion. Addition of IFNgamma to conditioned media from M. tb-infected monocytes (CoMTB) resulted in a 7-fold increase in MMP-9 activity detected by gelatin zymography (P<0.01). In contrast, tissue inhibitor of metalloproteinase (TIMP)-1 and -2 secretion, measured by ELISA, was suppressed. Dexamethasone abolished the synergistic increase in MMP-9 activity. Interleukin (IL)-1beta in CoMTB is a critical mediator of synergy with IFNgamma, and IL-1beta alone synergizes with IFNgamma to increase MMP-9 secretion from 51 +/- 31 to 762 +/- 136 U. IL-1beta activity is dependent on p38 mitogen-activated protein (MAPK) kinase, which was found to be phosphorylated in tissue specimens from patients with CNS-TB. Extracellular signal regulated kinase (Erk) and p38 MAPK activation did not affect IFNgamma signaling pathways. Inhibition of janus-activated kinase (JAK)-2 by 50 microM AG540 decreased MMP-9 secretion to 124 +/- 11.1 from 651 +/- 229 U of activity (P<0.01). However, signal transducer and activator of transcription (STAT)-3 but not STAT-1 phosphorylation was synergistically up-regulated by IFNgamma and CoMTB. In summary, synergy between IL-1beta and STAT-3 dependent IFNgamma signaling is key in control of up-regulation of MMP-9 activity in CNS-TB and may be a significant mechanism of brain tissue destruction.
AuthorsJames E Harris, Marc Fernandez-Vilaseca, Paul T G Elkington, Donna E Horncastle, Manuel B Graeber, Jon S Friedland
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 21 Issue 2 Pg. 356-65 (Feb 2007) ISSN: 1530-6860 [Electronic] United States
PMID17158965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Culture Media, Conditioned
  • Interleukin-1beta
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Dexamethasone
  • Interferon-gamma
  • Janus Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 9
Topics
  • Blotting, Western
  • Cell Line, Tumor
  • Culture Media, Conditioned (metabolism)
  • Dexamethasone (pharmacology)
  • Drug Synergism
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases (metabolism)
  • Humans
  • Immunohistochemistry
  • Interferon-gamma (pharmacology)
  • Interleukin-1beta (pharmacology)
  • Janus Kinases (metabolism)
  • Matrix Metalloproteinase 9 (metabolism)
  • Monocytes (drug effects, metabolism, microbiology)
  • Mycobacterium tuberculosis (growth & development)
  • Phosphorylation
  • Tissue Inhibitor of Metalloproteinase-1 (metabolism)
  • Tissue Inhibitor of Metalloproteinase-2 (metabolism)
  • Tuberculosis, Central Nervous System (metabolism)
  • Up-Regulation (drug effects)
  • p38 Mitogen-Activated Protein Kinases (metabolism)

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