IFN-γ synergizes with IL-1β to up-regulate MMP-9 secretion in a cellular model of central nervous system tuberculosis

Matrix metalloproteinase-9 (MMP-9) activity is implicated in pathogenesis of central nervous system tuberculosis (CNS-TB). IFN gamma, a key cytokine in TB, usually inhibits MMP-9 secretion. Addition of IFN gamma 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 beta in CoMTB is a critical mediator of synergy with IFN gamma, and IL-beta alone synergizes with IFN gamma to increase MMP-9 secretion from 51 +/- 31 to 762 +/- 136 U. IL-1 beta 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 gamma signaling pathways. Inhibition of janus-activated kinase (JAK)-2 by 50 mu M 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 gamma and CoMTB. In summary, synergy between Il-1 beta and STAT-3 dependent IFN gamma 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.