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 necrosi s factor (TNF)-alpha and NO production, which participate in apoptosis indu ction. ManLAM also modulates Ca+2- dependent intracellular events, and Ca+2 participates in apoptosis in different systems. Ca+2 was assessed for invo lvement in M, tuberculosis-induced macrophage apoptosis and for modulation by ManLAM, The role of Ca+2 was supported by the blockade of apoptosis by c AMP inhibitors and the Ca+2 chelator, BAPTA/AM, These agents also inhibited caspase-1 activation and cAMP-responsive element-binding protein transloca tion without affecting TNF-alpha production. Infection of macrophages with M, tuberculosis induced an influx of Ca+2 that was prevented by ManLAM, Sim ilarly, M. tuberculosis infection-altered mitochondrial permeability transi tion was prevented by ManLAM and BAPTA/AM. Finally, ManLAM and BAPTA/AM rev ersed the effects of nl. tuberculosis on p53 and Bcl-2 expression. ManLAM c ounteracts the alterations of calcium-dependent intracellular events that o ccur during M. tuberculosis-induced macrophage apoptosis.