Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens.

Suthanthiran, Manikkam; Anderson, Mary E.; Sharma, Vijay Kumar; Meister, Alton

doi:10.1073/pnas.87.9.3343

Cited by 336 publications

(189 citation statements)

References 46 publications

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“…In contrast to the positive effects of H 2 0 2 observed on gene expression, exposure of ESb-L cells to H202 was largely growth-inhibitory. This is consistent with the general requirement of thiols for lymphoid cells and with reports that withdrawal of thiols inhibits lymphocyte proliferation [25][26][27]. However, we observed that in a limited range of small H202 concentrations proliferation was enhanced when the cells were kept in a reducing environment, i.e.…”

Section: Discussionsupporting

confidence: 92%

“…In addition, intracellular ROI formation has been proposed to be required for lymphocyte proliferation since various antioxidants inhibit cell growth in response to mitogens [4,21,22]. By contrast, the proliferative response in other situations, such as in mixed lymphocyte reactions or IL-2-dependent cell growth, was found to be inhibited by prooxidants and promoted by antioxidants and exogenous thiols [5,[23][24][25][26][27][28]. Thus, it appears that certain lymphocyte functions are obviously promoted by prooxidant conditions whereas others are inhibited, suggesting the requirement of a delicate redox balance.…”

Section: Introductionmentioning

confidence: 99%

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Hydrogen peroxide as a potent activator of T lymphocyte functions

et al. 1995

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During inflammatory processes infiltrating cells produce large amounts of reactive oxygen intermediates (ROI). Increasing evidence suggests that ROI besides being cytotoxic may act as important mediators influencing various cellular and immunological processes. In this study, we have investigated the effects of hydrogen peroxide on several aspects of lymphocyte activation. In ESb‐L T lymphoma cells, micromolar concentrations of hydrogen peroxide rapidly induced activation of the transcription factor NF‐χB, whereas DNA‐binding activity of the transcription factor AP‐1 was virtually not affected. In addition, hydrogen peroxide induced early gene expression of interleukin‐2 (IL‐2) and the IL‐2 receptor α chain. The stimulation of IL‐2 expression was found to be conferred by a χB‐like cis‐regulatory region within the IL‐2 gene promoter. In contrast to these activating effects, addition of hydrogen peroxide was largely inhibitory on cell proliferation which is consistent with a general requirement of thiol compounds for lymphocyte proliferation. However, hydrogen peroxide significantly increased T cell proliferation when applied for a short period under reducing conditions. These data indicate that ROI may act as an important competence signal in T lymphocytes inducing early gene expression as well as cell proliferation.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Hydrogen peroxide as a potent activator of T lymphocyte functions

et al. 1995

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“…Based on these findings, we speculate that aberrant glutathione levels and redox homeostasis cause the increased division and small-cell phenotypes observed in the smt15-1 mutant. Supporting this hypothesis are numerous reports on the close association between cell proliferation and elevated glutathione levels and high GSH-GSSG ratios (Mauro et al, 1969;Kosower and Kosower, 1978;Suthanthiran et al, 1990;Sánchez-Fernández et al, 1997;May et al, 1998;Nkabyo et al, 2002). We have not been able to examine temporal redox control at a finer scale in wild-type and smt15-1 cells, as has been done in budding yeast, where redox and respiratory activity cycle with a period of about 40 min (Tu et al, 2005).…”

Section: Smt15 Glutathione and Cell Cycle Controlmentioning

confidence: 68%

Defects in a New Class of Sulfate/Anion Transporter Link Sulfur Acclimation Responses to Intracellular Glutathione Levels and Cell Cycle Control

et al. 2014

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We previously identified a mutation, suppressor of mating type locus3 15-1 (smt15-1), that partially suppresses the cell cycle defects caused by loss of the retinoblastoma tumor suppressor-related protein encoded by the MAT3 gene in Chlamydomonas reinhardtii. smt15-1 single mutants were also found to have a cell cycle defect leading to a small-cell phenotype. SMT15 belongs to a previously uncharacterized subfamily of putative membrane-localized sulfate/anion transporters that contain a sulfate transporter domain and are found in a widely distributed subset of eukaryotes and bacteria. Although we observed that smt15-1 has a defect in acclimation to sulfur-limited growth conditions, sulfur acclimation (sac) mutants, which are more severely defective for acclimation to sulfur limitation, do not have cell cycle defects and cannot suppress mat3. Moreover, we found that smt15-1, but not sac mutants, overaccumulates glutathione. In wild-type cells, glutathione fluctuated during the cell cycle, with highest levels in mid G1 phase and lower levels during S and M phases, while in smt15-1, glutathione levels remained elevated during S and M. In addition to increased total glutathione levels, smt15-1 cells had an increased reduced-to-oxidized glutathione redox ratio throughout the cell cycle. These data suggest a role for SMT15 in maintaining glutathione homeostasis that impacts the cell cycle and sulfur acclimation responses.

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“…A 10 -40% decrease in GSH content can completely inhibit lymphocyte activation in vitro (8). Indeed, the very fact that Tat modulates GSH biosynthesis in addition to suppressing the activity of manganese superoxide dismutase (27,41,42) may testify to the importance of redox regulation in HIV pathogenesis.…”

Section: Fig 3 Gcs-ls Protein Content Is Decreased In Liver and Erymentioning

confidence: 99%

Molecular Mechanism of Decreased Glutathione Content in Human Immunodeficiency Virus Type 1 Tat-transgenic Mice

Choi¹,

Liu²,

Kundu³

et al. 2000

Journal of Biological Chemistry

153

105

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Human immunodeficiency virus (HIV) progressively depletes GSH content in humans.Although the accumulated evidence suggests a role of decreased GSH in the pathogenesis of HIV, significant controversy remains concerning the mechanism of GSH depletion, especially in regard to envisioning appropriate therapeutic strategies to help compensate for such decreased antioxidant capacity. Tat, a transactivator encoded by HIV, is sufficient to cause GSH depletion in vitro and is implicated in AIDS-associated Kaposi's sarcoma and B cell lymphoma. In this study, we report a decrease in GSH biosynthesis with Tat, using HIV-1 Tat transgenic (Tat؉) mice. A significant decline in the total intracellular GSH content in liver and erythrocytes of Tat؉ mice was accompanied by decreased ␥-glutamylcysteine synthetase regulatory subunit mRNA and protein content, which resulted in an increased sensitivity of ␥-glutamylcysteine synthetase to feedback inhibition by GSH. Further study revealed a significant reduction in the activity of GSH synthetase in liver of Tat؉ mice, which was linearly associated with their GSH content. Therefore, Tat appears to decrease GSH in vivo, at least partially, through modulation of GSH biosynthetic enzymes. Human immunodeficiency virus (HIV)1 infection is associated with a systemic decrease in the GSH content in humans (1, 2). Such biochemical alteration appears to be a direct consequence of retroviral infection rather than a late and indirect consequence of advanced disease state, is progressive in nature, and often occurs in the absence of any symptoms associated with AIDS (2-5). The importance of this decreased GSH is suggested by the fact that decreased GSH can enhance HIV expression via activation of NF-B (4, 6, 7) and contribute to diverse immune dysfunctions found in AIDS, including the loss of CD4ϩ T lymphocytes via apoptosis (8 -11). In fact, such decline in the GSH content may play a role in the increased drug toxicity and oxidative damage, often found in HIV-infected individuals (12-15). Furthermore, increased GSH or other sulfhydryl compounds can inhibit viral replication (7, 16), HIV-1 reverse transcriptase activity (16,17), and the late stage of viral expression (18). GSH content may even predict the survival of HIV-seropositive (HIVϩ) individuals (19,20). Therefore, it is perhaps crucial to determine whether this decrease in GSH occurs through an accelerated loss of GSH or specific modulation of its synthesis, especially as it relates to potential therapeutic strategies to compensate for such decreased antioxidant capacity. However, despite over a decade of intensive research on this subject, the exact mechanism(s) causing decreased GSH content with HIV remains unclear.Cells maintain their high GSH content in part by reducing GSSG back to GSH, preventing the loss of GSH as GSSG (12). Also, GSH is synthesized from its amino acid constituents via two consecutive reactions catalyzed by ␥-glutamylcysteine synthetase (GCS; glutamate-cysteine ligase, EC 6.3.2.2) and GSH synthetase (GS; EC6.3.2.3). I...

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Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens.

Cited by 336 publications

References 46 publications

Hydrogen peroxide as a potent activator of T lymphocyte functions

Hydrogen peroxide as a potent activator of T lymphocyte functions

Defects in a New Class of Sulfate/Anion Transporter Link Sulfur Acclimation Responses to Intracellular Glutathione Levels and Cell Cycle Control

Molecular Mechanism of Decreased Glutathione Content in Human Immunodeficiency Virus Type 1 Tat-transgenic Mice

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