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

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-α (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 κB (NF-κB) 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-κB (BAY 11-7082). Furthermore, inhibition of NF-κB 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-κB.

Leishmania donovani-Induced Increase in Macrophage Bcl-2 Favors Parasite Survival

“…The involvement of the Bcl-2 family of proteins in preventing or inducing host-cell death has been explored for bacterial pathogens like Mycobacterium tuberculosis where infection upregulates Bcl-2 in mouse macrophages and THP-1 cells through the mitogen-activated protein kinase (MAPK) pathway (11). Another bacterial pathogen M. leprae , downregulates pro-apoptotic Bcl-2 family members Bad and Bak and upregulates the antiapoptotic Mcl-1 protein to prevent host-cell apoptosis (12).…”

The Control of Apoptotic Death in the Cells of Granulomatous Inflammatory Lesions from Mice with Latent Tuberculous Infection in the Ex Vivo Model

“…It has also been found that only virulent M. tuberculosis H37Rv induced expression of the Mcl-1 protein, an antiapoptotic member of the Bcl-2 family, after in vitro infection of human THP-1 cells [49]. In parallel, a weaker induction of TNFα expression was observed in human and mouse cells following in vitro infection with virulent than non-virulent strains [50][51][52]. Following in vivo infection of zebrafish (Danio rerio) juveniles with M. marinum, mycobacteria spread in their organisms due to the death of some granuloma macrophages and the release of mycobacteria into the extracellular environment, where they were later phagocyted by uninfected macrophages [28,53].…”

“…Natarajan and Sujatha observed a twofold increase in Bcl-2 levels as early as 24 h after in vitro infection of ТНР-1 monocyte-like cells with the virulent strain H37Rv of M. tuberculosis [52]. By contrast, blood mononuclear cells and human ТНР-1 cells infected in vitro with attenuated ВСG mycobacteria or non-virulent M. tuberculosis strain H37Rа had a considerable reduction in Bcl-2 protein after 24 h following infection [52,75]. We did not observe activation of Bcl-2 synthesis at hours 4-120 of analysis in the macrophages from bone barrow cell cultures and peritoneal exudates infected with BCG mycobacteria in vitro.…”

“…In a study of Mogga et al [74], it was not before week 16 following infection of mice with the virulent strain H37Rv of M. tuberculosis intraperitoneally that Bcl-2 protein became detectable by immunohistochemistry in lung tissue cells (about 5% of cells studied) that stained for mycobacterial antigens-but not for Вах protein. Natarajan and Sujatha observed a twofold increase in Bcl-2 levels as early as 24 h after in vitro infection of ТНР-1 monocyte-like cells with the virulent strain H37Rv of M. tuberculosis [52]. By contrast, blood mononuclear cells and human ТНР-1 cells infected in vitro with attenuated ВСG mycobacteria or non-virulent M. tuberculosis strain H37Rа had a considerable reduction in Bcl-2 protein after 24 h following infection [52,75].…”

“…Apoptosis leads not only to disposal of digested apoptotic cells with mycobacteria and their elimination in phagosomes, but also to an efficient processing of mycobacterial antigens used by antigen-presenting cells for the maintenance and enhancement of the immune response to the pathogen [24]. It has been established that in vitro infection of different cell types with non-virulent strains of mycobacteria led these cells to rapid death by TNFα-induced receptor-dependent apoptosis [48,52,65]. However, our previous studies using the ex vivo model of granulomatous inflammatory lesions in mice did not reveal, at any time of latent tuberculous infection, morphological signs of apoptotic or necrotic death in granuloma macrophages or dendritic cells differently loaded with mycobacteria of the attenuated BCG strain [55][56][57].…”