Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca+2-dependent cell signaling.
Mycobacterium tuberculosis-induced macrophage apoptosis can be inhibited by mannosylated lipoarabinomannan (ManLAM), although it induces tumor necrosis factor (TNF)-alpha and NO production, which participate in apoptosis induction. ManLAM also modulates Ca(+2)-dependent intracellular events, and Ca(+2) participates in apoptosis in different systems. Ca(+2) was assessed for involvement in M. tuberculosis-induced macrophage apoptosis and for modulation by ManLAM. The role of Ca(+2) was supported by the blockade of apoptosis by cAMP inhibitors and the Ca(+2) chelator, BAPTA/AM. These agents also inhibited caspase-1 activation and cAMP-responsive element-binding protein translocation without affecting TNF-alpha production. Infection of macrophages with M. tuberculosis induced an influx of Ca(+2) that was prevented by ManLAM. Similarly, M. tuberculosis infection-altered mitochondrial permeability transition was prevented by ManLAM and BAPTA/AM. Finally, ManLAM and BAPTA/AM reversed the effects of M. tuberculosis on p53 and Bcl-2 expression. ManLAM counteracts the alterations of calcium-dependent intracellular events that occur during M. tuberculosis-induced macrophage apoptosis.
Rojas
M
M
Grupo de Inmunología Celular e Inmunogenética, Laboratorio Central de Investigaciones, Centro de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
García
L F
LF
Nigou
J
J
Puzo
G
G
Olivier
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D005434:Flow Cytometry; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D008358:Mannose / Q000378:metabolism; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000502:physiology*
D008070:Lipopolysaccharides; C050016:lipoarabinomannan; D008358:Mannose; D002118:Calcium