Mitogen-activated protein kinases mediate the production of B-cell lymphoma 2 protein by Mycobacterium tuberculosis in monocytes.

Natarajan, P.L.; Narayanan, S.

Biochemistry ( Moscow ); 2011; 76; 938-950.   

Abstract: Changes in the levels of antiapoptotic protein B-cell lymphoma 2 (Bcl-2) protein has been reported in murine and human tuberculosis. We investigated the role of mitogen-activated protein kinase pathways in the production of Bcl-2 protein in THP-1 human monocytes infected with Mycobacterium tuberculosis H37Rv and H37Ra. Analysis of phosphorylation profiles of mitogen-activated protein kinase kinase-1, extracellular-signal regulated kinase 1/2, mitogen-activated protein kinase kinase 3/6, and p38 mitogen-activated protein kinase; B_cell lymphoma 2 kinetics; and tumor necrosis factor-a (TNF-α) secretion levels showed variation between the two strains. Mycobacterium tuberculosis H37Rv induced higher Bcl-2 and lower TNF-α levels, whereas H37Ra the reverse. The strains also differed in their usage of CD14 and human leukocyte antigen-DR receptors in mediating extracellular-signal regulated kinase 1/2 and p38 mitogen-activated protein kinase activation. Mycobacterium tuberculosis H37Rv- and H37Ra- induced Bcl-2 production was reduced by specific inhibitors of mitogen-activated protein kinase kinase-1 (PD98059) and p38 (SB203580), but increased by nuclear factor   ? B (NF-?B) inhibitor (BAY 11-7082). TNF-α production by both strains was reduced in the presence of specific inhibitors of mitogen-activated protein kinase kinase-1 (PD98059), p38 (SB203580), and NF-?B (BAY 11-7082). Furthermore, inhibition of NF-?B was accompanied by an increase in strain-induced extracellular-signal regulated kinase 1/2 phosphorylation. Collectively, these results indicate for the first time that the production of Bcl-2 and TNF-α by M. tuberculosis H37Rv/H37Ra-infected THP-1 human monocytes is mediated through mitogen-activated protein kinases and NF-?B.

Keywords : M. tuberculosis , ERK, p38 MAPK, Bcl-2 production, NF-?B

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