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.
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Authors | James E Harris, Marc Fernandez-Vilaseca, Paul T G Elkington, Donna E Horncastle, Manuel B Graeber, Jon S Friedland |
Journal | FASEB 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 |
PMID | 17158965
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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