title: The Mycobacterium tuberculosis early secreted antigenic target of 6 kDa inhibits T cell interferon-γ production through the p38 mitogen-activated protein kinase pathway.
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.
authors.affiliation: Center for Pulmonary and Infectious Disease Control, University of Texas Health Science Center, Tyler, Texas 75708, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Xisheng
authors.initials: X
authors.lastname: Wang
authors.forename: Peter F
authors.initials: PF
authors.lastname: Barnes
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.forename: James C
authors.initials: JC
authors.lastname: Townsend
authors.forename: Buka
authors.initials: B
authors.lastname: Samten
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055985:Latent Tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D004791:Enzyme Inhibitors; C508609:IL10 protein, human; D007093:Imidazoles; D020381:Interleukin-17; D011725:Pyridines; D016753:Interleukin-10; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C093642:SB 203580