Activation of JAK2/STAT1-alpha-dependent signaling events during Mycobacterium tuberculosis-induced macrophage apoptosis.
Induction of apoptosis by Mycobacterium tuberculosis in murine macrophage involves TNF-alpha 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-alpha phosphorylation, and STAT1-alpha nuclear translocation. Inhibitors of PTK (AG-126), or JAK2 (AG-490) inhibited TNF-alpha and NO production, caspase 1 activation and apoptosis, suggesting that M. tuberculosis-induction of these events depends on JAK2/STAT1-alpha 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-alpha pathway suggests that M. tuberculosis might mimic macrophage-activating stimuli.
Rojas
Mauricio
M
Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia, Cra 51D No. 62-29 Lab 283, Medellín, Colombia. mrojas1@epm.net.co
Olivier
Martin
M
García
Luis F
LF
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050832:Interferon-Stimulated Gene Factor 3; D053614:Janus Kinase 2; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008809:Mice, Inbred C3H; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D009569:Nitric Oxide / Q000096:biosynthesis; D010587:Phagocytosis; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D050832:Interferon-Stimulated Gene Factor 3; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C079868:gamma interferon activation factor; D009569:Nitric Oxide; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D020169:Caspases