Abstract
We reported previously that the early secreted antigenic target of 6 kDa (ESAT-6) from Mycobacterium tuberculosis directly inhibits human T cell IFN-γ production and proliferation in response to stimulation with anti-CD3 and anti-CD28. To determine the mechanism of this effect, we treated T cells with kinase inhibitors before stimulation with ESAT-6. Only the p38 MAPK inhibitor, SB203580, abrogated ESAT-6-mediated inhibition of IFN-γ production in a dose-dependent manner. SB203580 did not reverse ESAT-6-mediated inhibition of IL-17 and IL-10 production, suggesting a specific effect of SB203580 on IFN-γ production. SB203580 did not act through inhibition of AKT (PKB) as an AKT inhibitor did not affect ESAT-6 inhibition of T cell IFN-γ production and proliferation. ESAT-6 did not reduce IFN-γ production by expanding FoxP3(+) T regulatory cells. Incubation of T cells with ESAT-6 induced phosphorylation and increased functional p38 MAPK activity, but not activation of ERK or JNK. Incubation of peripheral blood mononuclear cells with ESAT-6 induced activation of p38 MAPK, and inhibition of p38 MAPK with SB203580 reversed ESAT-6 inhibition of M. tuberculosis-stimulated IFN-γ production by peripheral blood mononuclear cells from subjects with latent tuberculosis infection. Silencing of p38α MAPK with siRNA rendered T cells resistant to ESAT-6 inhibition of IFN-γ production. Taken together, our results demonstrate that ESAT-6 inhibits T cell IFN-γ production in a p38 MAPK-dependent manner.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Bacterial / genetics
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Antigens, Bacterial / immunology
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Antigens, Bacterial / metabolism*
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Bacterial Proteins / genetics
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Bacterial Proteins / immunology
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Bacterial Proteins / metabolism*
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Cell Proliferation / drug effects
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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Gene Silencing
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Humans
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Imidazoles / pharmacology
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Interferon-gamma / biosynthesis*
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-10 / genetics
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Interleukin-17 / genetics
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Latent Tuberculosis / genetics
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Latent Tuberculosis / immunology
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Latent Tuberculosis / metabolism*
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / immunology
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MAP Kinase Kinase 4 / metabolism
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Mycobacterium tuberculosis / genetics
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Mycobacterium tuberculosis / immunology
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Mycobacterium tuberculosis / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridines / pharmacology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Antigens, Bacterial
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Bacterial Proteins
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ESAT-6 protein, Mycobacterium tuberculosis
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Enzyme Inhibitors
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IL10 protein, human
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Imidazoles
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Interleukin-17
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Pyridines
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Interleukin-10
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Interferon-gamma
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Proto-Oncogene Proteins c-akt
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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SB 203580