Matrix metalloproteinase-9 (MMP-9) activity is implicated in pathogenesis of central nervous system tuberculosis (CNS-TB). IFN, a key cytokine in TB, usually inhibits MMP-9 secretion. Addition of IFN 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)-1 in CoMTB is a critical mediator of synergy with IFN, and IL-1 alone synergizes with IFN to increase MMP-9 secretion from 51 ± 31 to 762 ± 136 U. IL-1 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 IFN signaling pathways. Inhibition of janus-activated kinase (JAK)-2 by 50 µM 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 IFN and CoMTB. In summary, synergy between IL-1 and STAT-3 dependent IFN 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.--Harris, J. E., Fernandez-Vilaseca, M., Elkington, P. T. G., Horncastle, D. E., Graeber, M. B., and Friedland, J. S. IFN synergizes with IL-1 to up-regulate MMP-9 secretion in a cellular model of central nervous system tuberculosis.