title: TNF-alpha and IL-10 modulate the induction of apoptosis by virulent Mycobacterium tuberculosis in murine macrophages.
abstract: The Bcg/Nramp1 gene controls early resistance and susceptibility of macrophages to mycobacterial infections. We previously reported that Mycobacterium tuberculosis-infected (Mtb) B10R (Bcgr) and B10S (Bcgs) macrophages differentially produce nitric oxide (NO-), leading to macrophage apoptosis. Since TNF-alpha and IL-10 have opposite effects on many macrophage functions, we determined the number of cells producing TNF-alpha and IL-10 in Mtb-infected or purified protein derivative-stimulated B10R and B10S macrophages lines, and Nramp1+/+ and Nramp1-/- peritoneal macrophages and correlated them with Mtb-mediated apoptosis. Mtb infection and purified protein derivative treatment induced more TNF-alpha+Nramp1+/+ and B10R, and more IL-10+Nramp1-/- and B10S cells. Treatment with mannosylated lipoarabinomannan, which rescues macrophages from Mtb-induced apoptosis, augmented the number of IL-10 B10R+ cells. Anti-TNF-alpha inhibited apoptosis, diminished NO- production, p53, and caspase 1 activation and increased Bcl-2 expression. In contrast, anti-IL-10 increased caspase 1 activation, p53 expression, and apoptosis, although there was no increment in NO- production. Murine rTNF-alpha induced apoptosis in noninfected B10R and B10S macrophages that was reversed by murine rIL-10 in a dose-dependent manner with concomitant inhibition of NO- production and caspase 1 activation. NO- and caspase 1 seem to be independently activated in that aminoguanidine did not affect caspase 1 activation and the inhibitor of caspase 1, Tyr-Val-Ala-Asp-acylooxymethylketone, did not block NO- production; however, both treatments inhibited apoptosis. These results show that Mtb activates TNF-alpha- and IL-10-dependent opposite signals in the induction of macrophage apoptosis and suggest that the TNF-alpha-IL-10 ratio is controlled by the Nramp1 background of resistance/susceptibility and may account for the balance between apoptosis and macrophage survival.
authors.affiliation: Grupo de Inmunología Celular e Inmunogenética, Laboratorio Central de Investigaciones, Centro de Investigaciones Médicas. Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
authors.forename: M
authors.initials: M
authors.lastname: Rojas
authors.forename: M
authors.initials: M
authors.lastname: Olivier
authors.forename: P
authors.initials: P
authors.lastname: Gros
authors.forename: L F
authors.initials: LF
authors.lastname: Barrera
authors.forename: L F
authors.initials: LF
authors.lastname: García
mesh_terms: D000818:Animals; D017209:Apoptosis; D020170:Caspase 1 / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008815:Mice, Inbred Strains; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014373:Tuberculin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D019253:Proto-Oncogene Proteins c-bcl-2; D014373:Tuberculin; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D016753:Interleukin-10; D009569:Nitric Oxide; D020170:Caspase 1; C004479:pimagedine