Activation of JAK2/STAT1-α-dependent signaling events during Mycobacterium tuberculosis-induced macrophage apoptosis

Induction of apoptosis by Mycobacterium tuberculosis in murine macrophage involves TNF-α and nitric oxide (NO) production and caspase cascade activation; however, the intracellular signaling pathways implicated remain to be established. Our results indicate that infection of the B10R murine macrophage line with M. tuberculosis induces apoptosis independent of mycobacterial phagocytosis and that M. tuberculosis induces protein tyrosine kinase (PTK) activity, JAK2/STAT1-α phosphorylation, and STAT1-α nuclear translocation. Inhibitors of PTK (AG-126), or JAK2 (AG-490) inhibited TNF-α and NO production, caspase 1 activation and apoptosis, suggesting that M. tuberculosis-induction of these events depends on JAK2/STAT1-α activation. In addition, we have obtained evidence that ManLAM capacity to inhibit M. tuberculosis-induced apoptosis involves the activation of the PTP SHP-1. The finding that M. tuberculosis infection activate JAK2/STAT1-α pathway suggests that M. tuberculosis might mimic macrophage-activating stimuli.