title: 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.
authors.affiliation: Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College, Du Cane Rd., London, W12 0NN, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Harris
authors.forename: Marc
authors.initials: M
authors.lastname: Fernandez-Vilaseca
authors.forename: Paul T G
authors.initials: PT
authors.lastname: Elkington
authors.forename: Donna E
authors.initials: DE
authors.lastname: Horncastle
authors.forename: Manuel B
authors.initials: MB
authors.lastname: Graeber
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D010766:Phosphorylation; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D020306:Tuberculosis, Central Nervous System / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D003907:Dexamethasone; D007371:Interferon-gamma; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9