title: Mycobacterial di-O-acyl trehalose inhibits Th-1 cytokine gene expression in murine cells by down-modulation of MAPK signaling.
abstract: Protection against tuberculosis (TB) is based on cell-mediated immune responses. TB is often characterized by immunological dysfunction of peripheral blood mononuclear cells, especially at chronic stages. Lipids from the Mycobacterium tuberculosis cell wall have been shown to produce various suppressive effects on cell-mediated immunity. The cell-surface lipid di-O-acyl-trehalose (DAT) is able to inhibit T-cell proliferation and cytokine secretion in cells from naïve mice. In the present study, we addressed the mechanisms involved in the suppressive effect caused by DAT. We found that DAT decreased the proliferation of spleen cells induced with PMA-ionomycin, suggesting that the suppressive mechanisms target intracellular functions just after phospholipase C-gamma activation. Addressing this possibility, the effect of DAT was found to involve down-modulation of the di-acyl glycerol-dependent activation of the MAPK-ERK1/2 pathway, one of the crucial signaling pathways leading to adaptive cell immune response against TB. Moreover, the inhibitory effect of DAT on proliferation was reproduced in antigen-stimulated T cells from M. tuberculosis-infected mice, involving the lowering of Th1-type cytokine transcription levels. The present findings thus reveal a new kind of bioactivity for a long-known M. tuberculosis cell wall lipid, DAT.
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, DF México, Mexico.
authors.forename: José Prisco
authors.initials: JP
authors.lastname: Palma-Nicolás
authors.forename: Rogelio
authors.initials: R
authors.lastname: Hernández-Pando
authors.forename: Erika
authors.initials: E
authors.lastname: Segura
authors.forename: María J
authors.initials: MJ
authors.lastname: Ibarra-Sánchez
authors.forename: Iris
authors.initials: I
authors.lastname: Estrada-García
authors.forename: Alejandro
authors.initials: A
authors.lastname: Zentella-Dehesa
authors.forename: Luz M
authors.initials: LM
authors.lastname: López-Marín
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D015536:Down-Regulation; D006017:Glycolipids / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019907:Mycobacterium fortuitum / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014158:Transcription, Genetic; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D016207:Cytokines; D006017:Glycolipids; C082079:glycolipid IV, Mycobacterium tuberculosis