Mycobacterial di-O-acyl trehalose inhibits Th-1 cytokine gene expression in murine cells by down-modulation of MAPK signaling

Palma-Nicolás, José Prisco; Hernández-Pando, Rogelio; Segura, Erika; Ibarra-Sánchez, Marı́a de Jesús; Estrada-Garcia, Iris; Zentella‐Dehesa, Alejandro; López-Marı́n, Luz M.

doi:10.1016/j.imbio.2009.03.010

Cited by 18 publications

(14 citation statements)

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“…We did not observe any effect on p38 phosphorylation in TCR/CD28 induced cells of healthy individual after treatment with M. tuberculosis antigen whereas in pulmonary TB patients Ag85A and ESAT-6 significantly curtailed p38 phosphorylation. Palma-Nicholas [ 22 ] reported down-modulation of MAPK–ERK1/2 pathway in total spleen cells from naive BALB/c mice by the cell-surface lipid di-O-acyl-trehalose (DAT), which further leads to lowering of Th-1 type cytokine production. As per our knowledge ours is the first study where differential modulation of TCR or TCR/CD28 induced downstream signalling events like MAPKs in the PBMCs of pulmonary TB patients has been observed.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events

et al. 2015

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BackgroundMycobacterium tuberculosis (M. tuberculosis) modulates host immune response, mainly T cell responses for its own survival leading to disease or latent infection. The molecules and mechanisms utilized to accomplish immune subversion by M. tuberculosis are not fully understood. Understanding the molecular mechanism of T cell response to M. tuberculosis is important for development of efficacious vaccine against TB.MethodsHere, we investigated effect of M. tuberculosis antigens Ag85A and ESAT-6 on T cell signalling events in CD3/CD28 induced Peripheral blood mononuclear cells (PBMCs) of PPD+ve healthy individuals and pulmonary TB patients. We studied CD3 induced intracellular calcium mobilization in PBMCs of healthy individuals and TB patients by spectrofluorimetry, CD3 and CD28 induced activation of mitogen activated protein kinases (MAPKs) in PBMCs of healthy individuals and TB patients by western blotting and binding of transcription factors NFAT and NFκB by Electrophorectic mobility shift assay (EMSA).ResultsWe observed CD3 triggered modulations in free intracellular calcium concentrations in PPD+ve healthy individuals and pulmonary TB patients after the treatment of M. tuberculosis antigens. As regards the downstream signalling events, phosphorylation of MAPKs, Extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 was curtailed by M. tuberculosis antigens in TB patients whereas, in PPD+ve healthy individuals only ERK1/2 phosphorylation was inhibited. Besides, the terminal signalling events like binding of transcription factors NFAT and NFκB was also altered by M. tuberculosis antigens. Altogether, our results suggest that M. tuberculosis antigens, specifically ESAT-6, interfere with TCR/CD28-induced upstream as well as downstream signalling events which might be responsible for defective IL-2 production which further contributed in T-cell unresponsiveness, implicated in the progression of disease.ConclusionTo the best of our knowledge, this is the first study to investigate effect of Ag85A and ESAT-6 on TCR- and TCR/CD28- induced upstream and downstream signalling events of T-cell activation in TB patients. This study showed the effect of secretory antigens of M. tuberculosis in the modulation of T cell signalling pathways. This inflection is accomplished by altering the proximal and distal events of signalling cascade which could be involved in T-cell dysfunctioning during the progression of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-015-0128-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events

et al. 2015

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“…Only recently the role of acylated trehaloses as virulence factors has been unraveled. DAT downregulates T-cell proliferation and the production of Th-1 cytokines; this effect is associated with disruption of the MAPK signaling pathway [14, 36]. DAT also affects macrophage functions, downregulating iNOS and nitric oxide production [15].…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial glycolipid Di-O-acyl trehalose promotes a tolerogenic profile in dendritic cells

et al. 2018

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Due to prolonged coevolution with the human being, Mycobacterium tuberculosis has acquired a sophisticated capacity to evade host immunity and persist in a latent state in the infected individual. As part of this evolutive process, mycobacteria have developed a highly complex cell wall that acts as a protective barrier. Herein we studied the effects of Di-O-acyl trehalose, a cell-wall glycolipid of virulent mycobacteria on murine bone marrow-derived dendritic cells. We have demonstrated that Di-O-Acyl-trehalose promotes a tolerogenic phenotype in bone marrow-derived murine DCs activated with mycobacterial antigens and Toll-like receptor agonists. This phenotype included low expression of antigen presentation and costimulatory molecules and altered cytokine production with downregulation of IL-12 and upregulation of IL-10, an anti-inflammatory cytokine. Additional markers of tolerogenicity were the expression of Indoleamine 2,3-dioxygenase and CD25. Furthermore, Di-O-Acyl-Trehalose promoted the expansion of FoxP3+ regulatory T lymphocytes. A better understanding of mycobacterial cell-wall components involved in the evasion of immunity is a prerequisite to designing better strategies to fight tuberculosis.

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“…As PMA and ionomycin are able to activate Th cells within 4-6 h, they were selected in the present study to minimize incubation time of PBMCs in vitro and maintain cell viability. As PMA and ionomycin are able to down regulate CD4 expression, Th1 and Th2 lymphocytes with CD3 + and CD8were labeled in the present study, a detection method that has been used in previous studies (16,35). Additionally, trypan blue staining was performed to assess the extent of cell death over the course of the present study.…”

Section: Discussionmentioning

confidence: 99%

Morphine and ketamine treatment suppress the differentiation of T helper cells of patients with colorectal cancer in�vitro

Hou

Zhou

et al. 2018

Exp Ther Med

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There have been conflicting reports regarding the effects of anesthetic and analgesic drugs on immune function in patients with cancer. The aim of the present study was to investigate changes to T helper (Th) cell populations in patients with colorectal cancer (CRC) and to assess the effects of morphine and ketamine on the differentiation of Th cells harvested from patients with CRC in vitro. Peripheral blood samples were extracted from 20 patients with CRC and 20 healthy participants. Peripheral blood mononuclear cells were isolated and incubated in a solution containing phorbol-myristate-acetate (PMA) and ionomycin in the presence or absence of morphine or various ketamine concentrations (25, 50, and 100 µM). Samples were analyzed 4 h later. Th1 and Th2 cells were significantly increased by PMA and ionomycin stimulation; however, Th1 cells and the Th1/Th2 ratio in PMA and ionomycin treatments were significantly decreased in the CRC group compared with the control group. Following incubation with PMA and ionomycin, morphine significantly decreased Th1 cells and the Th1/Th2 ratio in the CRC group. Ketamine did not significantly affect levels of Th1 or Th2 cells or the Th1/Th2 ratio at a concentration of 25 µM; however, a significant increase in the Th1/Th2 ratio was observed at a concentration of 50 µM and, at 100 µM, a significant decrease in Th1 and Th2 cells and an increase in the Th1/Th2 ratio were observed. The present study suggests that CRC may shift the balance of Th1/Th2 towards Th2 by inducing an immunological response, morphine is able to suppress the differentiation of Th cells and decreases the Th1/Th2 ratio, and ketamine may affect the differentiation of Th cells in a dose-dependent manner.

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Mycobacterial di-O-acyl trehalose inhibits Th-1 cytokine gene expression in murine cells by down-modulation of MAPK signaling

Cited by 18 publications

References 34 publications

Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events

Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events

Mycobacterial glycolipid Di-O-acyl trehalose promotes a tolerogenic profile in dendritic cells

Morphine and ketamine treatment suppress the differentiation of T helper cells of patients with colorectal cancer in�vitro

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