UMLS:C1260386 - FACTA Search

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Query: UMLS:C1260386 (GSH)
38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By activating murine lymphocytes with anti-CD3 antibodies for 1 to 2 days, we generated a subset of activated killer cells, namely CD3-AK-. CD3-AK- mediated the slow lysis (20-h 125I-UdR release assay) of allogeneic P815 but had little effect on syngeneic HFL/b cells. Addition of IL-2 (murine or human) or an IL-2 inducer such as PMA in the assay medium induced the cytolytic activity of CD3-AK- on HFL/b. The activating effect of murine IL-2 and PMA on CD3-AK- was decreased by anti-murine IL-2 mAb. Although anti-murine IL-4 mAb alone did not show any effect, it enhanced the inhibitory effect of anti-IL-2 mAb, suggesting that IL-2 and IL-4 may have a synergistic effect on the cytolytic activity of CD3-AK-. Incubation of CD3-AK- with L-buthionine-(SR)-sulfoximine (BSO), an inhibitor of de novo glutathione (GSH) synthesis, decreased cellular GSH levels and inhibited the cytolytic activity of CD3-AK-, in a concentration-dependent manner. This inhibitory effect of BSO was not primarily due to a general cytotoxic effect and was positively correlated with the requirement for IL-2 for the CD3-AK(-)-mediated killing of the target cells. Incubation of CD3-AK- with GSH or 2-ME, which increased the level of cellular GSH, reversed the inhibitory effect of BSO. These results suggest that cellular GSH may regulate the effect of lymphokine(s) such as IL-2 and thus affect the differentiation of activated primary cytotoxic lymphocytes.
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PMID:Regulation by glutathione of the effect of lymphokines on differentiation of primary activated lymphocytes. Influence of glutathione on cytotoxic activity of CD3-AK-. 182 13

N-Acetyl-L-cysteine (NAC) is an antioxidant precursor of intracellular glutathione (GSH), usually given in human as a mucolytic agent. In vitro, NAC and GSH have been shown to act on T cells by increasing interleukin (IL) 2 production, synthesis and turnover of IL-2 receptors, proliferation, cytotoxic properties, and resistance to apoptosis. We report here that NAC and GSH decrease in a dose-dependent manner human IL-4 production by stimulated peripheral blood T cells and by T helper (Th) 0- and Th2-like T cell clones. This effect was associated with a decrease in IL-4 messenger RNA transcription. In contrast, NAC and GSH had no effect on interferon gamma and increased IL-2 production and T cell proliferation. A functional consequence was the capacity of NAC and GSH to selectively decrease in a dose-dependent manner IL-4-induced immunoglobulin (Ig) E and IgG4 production by human peripheral blood mononuclear cells. Interestingly, NAC and GSH also acted directly on purified tonsillar B cells by decreasing the mature epsilon messenger RNA, hence decreasing IgE production. In contrast, IgA and IgM production were not affected. At the same time, B cell proliferation was increased in a dose-dependent manner. Not all antioxidants tested but only SH-bearing molecules mimicked these properties. Finally, when given orally to mice, NAC decreased both IgE and IgG1 antibody responses to ovalbumin. These results demonstrate that NAC, GSH, and other thiols may control the production of both the Th2-derived cytokine IL-4 and IL-4-induced Ig in vitro and in vivo.
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PMID:Thiols decrease human interleukin (IL) 4 production and IL-4-induced immunoglobulin synthesis. 750 23

Glutathione (GSH) was shown to regulate the generation of IL-2-dependent activated killer cells. Generation of alpha CD3-activated killer cells CD3-AK was regulated by both IL-2 and IL-4. In the present study the role of GSH in the regulation of IL-4-dependent CD3-AK cells was examined. After initial activation of mouse splenocytes by alpha CD3, subculturing the CD3-AK cells in IL-4 resulted in the production of IL-4-dependent killer cells whose proliferative and cytolytic activities were abrogated by alpha IL-4 antibody 11B11. Adding graded doses of BSO, a GSH synthetase inhibitor, into CD3-AK cells culturing in IL-4 resulted in the reduction of their proliferative and cytotoxic responses. Adding exogenous GSH reversed the inhibitory effect of BSO and restored the proliferation and cytolytic activity of IL-4-dependent CD3-AK cells. The dose requirement for BSO to affect the IL-4-dependent CD3-AK cells was similar to that for the IL-2-dependent CD3-AK cells. These findings indicate that GSH also regulates the function of IL-4 in the activation and differentiation of CD3-AK cells. To further study the mechanism for the GSH regulation of the cytolytic activity of CD3-AK cells, we found that BSO did not reduce the production of BLT-esterase which contained mostly the cytolytic granules; in fact, BLT-esterase production was often increased by BSO. Furthermore, the exocytosis and effector function of cytolytic granules were also not affected by BSO. Thus it appears that reduction of cellular GSH may result in the accumulation of defective cytolytic granules which accounts for the reduction of killer cell cytolytic activity.
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PMID:Regulation by glutathione of the activation and differentiation of IL-4-dependent activated killer cells. 833 Mar 19

The present study explores a model for tumor cell-induced immunosuppression and reversal of suppression by cytokines and other pharmacological agents. To simulate tumor-cell-induced suppression, a panel of suppressor agents which included CsA (cyclosporin A), SSP (staurosporine), BSO (L-buthionine-[S,R]-sulfoximine) and PMA, and a panel of anti-suppressor agents which included IL-2, IL-4, GSH (glutathione) and amiloride, were tested. These suppressor/anti-suppressor agents acted differently on four specific sites of the immune arm that affected the alpha CD3-induced T cell proliferative and cytotoxic responses. They included (1) IL-2 production, (2) PKC-regulated cytolytic granule production, (3) GSH-regulated maturation of functional granules, and (4) granule exocytosis. When a single suppressor agent was used, all the suppressor agents tested in this study inhibited the generation of alpha CD3-induced activated killer cells (CD3-AK), whereas alpha CD3-induced proliferation was inhibited by CsA, BSO, and EL-4 tumor cells. Except for EL-4, suppression induced by a single suppressor agent could be corrected by an appropriate single anti-suppressor agent. Multiple suppressor agents induced profound suppression of CD3-AK response. In most cases, multiple anti-suppressor agents were required to correct the immune defects induced by multiple suppressor agents. Finally, EL-4 tumor-cell-induced immunosuppression could not be corrected by any single anti-suppressor agent tested, but a combination of IL-4, GSH and amiloride fully restored the CD3-AK response. These results suggest that tumor cells may induce multiple immune defects that require multiple anti-suppressor agents for correcting the defects to restore the host immunocompetence.
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PMID:Reversal of multiple-site tumor cell-induced immunosuppression by specific cytokines and pharmacological agents. 853 Feb 53

We previously demonstrated that the broad-spectrum caspase inhibitor, zVAD-fmk, totally deviated apoptosis to necrosis in B lymphocytes. We report here that, in contrast with zVAD-fmk, IL-4 protected B cells from spontaneous and from dexamethasone-induced apoptosis and actually maintained cell viability. This was assessed by morphological and biochemical criteria and accompanied by the maintenance of mitochondrial transmembrane potential (DeltaPsiCm) and elevated glutathione (GSH) levels. Under these conditions, zVAD-fmk also totally inhibited apoptosis in thymocytes, but it partly preserved cell viability with a parallel increase in the percentage of cells exhibiting high DeltaPsiCm and elevated GSH levels. Nevertheless, non-rescued cells were deviated to necrosis. Therefore, the pathway leading to either apoptosis or necrosis appears to involve common mitochondrial dysfunctions which could not be reversed by caspase inhibition, suggesting that the pharmacological inhibition of cell death should occur at an earlier stage.
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PMID:IL-4 inhibits apoptosis and prevents mitochondrial damage without inducing the switch to necrosis observed with caspase inhibitors. 1046 56

Activation-induced death of inflammatory cells (AICD) has an important function in immune maintenance. Type 1 Th cells are known to be more susceptible to AICD than Th2 cells. In the current study we examined whether NO-induced apoptosis also preferentially eliminates Th1 cells over Th2 cells. Naive human Th lymphocytes (CD4(+)CD45RO(-)) were activated in vitro for 1 week in the presence of IL-12 plus anti-IL-4 or IL-4 plus anti-IL-12 to generate Th1- and Th2-polarized cultures respectively. Cultures were exposed to the NO donors Spermine-nonoate (Sper) and DPTA-nonoate to study NO-induced apoptosis. We found that NO preferentially induced apoptosis in Th1-polarized cells as demonstrated by Annexin staining in the presence of 10 microM Sper (70 +/- 16 versus 23 +/- 4.4% in Th2 cells P: < 0.01) and by DioC6 staining (38 +/- 10 versus 11 +/- 5% in Th2 cells, P: < 0.01). The mechanism of NO-induced apoptosis in Th1/Th2-polarized cells was distinct from AICD and Fas-induced apoptosis. Differential sensitivity between Th1- and Th2-polarized cultures originated at the level of intracellular glutathione (GSH) metabolism. GSH levels were higher in Th2 cells (1.6 +/- 0.2-fold Th1, P: < 0.01). High intracellular GSH in Th2-polarized cells did not account for reduced susceptibility to NO per se, since the inhibition of gamma-glutamyltrans-peptidase (gamma-GT), which is involved in GSH import, sensitized Th2 cells to NO-induced apoptosis without GSH depletion. Therefore, higher activity of gamma-GT in Th2 cells (2.1 +/- 0.4-fold Th1, P: < 0.001) specifically protects Th2 cells against NO-induced apoptosis. Preferential NO-induced elimination of human Th1 cells at sites of inflammation may thus select Th2 cells and contribute to immune deviation.
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PMID:Resistance of activated human Th2 cells to NO-induced apoptosis is mediated by gamma-glutamyltranspeptidase. 1128 91

The thiol antioxidant N-acetyl- L-cysteine (NAC), known as a precursor of glutathione (GSH), is used in AIDS treatment trials, as a chemoprotectant in cancer chemotherapy and in treatment of chronic bronchitis. In vitro, GSH and NAC are known to enhance T cell proliferation, production of IL-2 and up-regulation of the IL-2 receptor. The 120-kD CD30 surface antigen belongs to the tumour necrosis factor (TNF) receptor superfamily. It is expressed by activated T helper (Th) cells and its expression is sustained in Th2 cells. We have analysed the effect of GSH and NAC on the cytokine profile and CD30 expression on human allergen-specific T cell clones (TCC). TCC were stimulated with anti-CD3 antibodies in the presence of different concentrations of GSH and NAC. Both thiols caused a dose dependent down-regulation of IL-4, IL-5 and IFN-gamma levels in Th0 and Th2 clones, with the most pronounced decrease of IL-4. Furthermore, they down-regulated the surface expression of CD30, and the levels of soluble CD30 (sCD30) in the culture supernatants were decreased. In contrast, the surface expression of CD28 or CD40 ligand (CD40L) was not significantly changed after treatment with 20 m M NAC. These results indicate that GSH and NAC favour a Th1 response by a preferential down-regulation of IL-4. In addition, the expression of CD30 was down regulated by GSH and NAC, suggesting that CD30 expression is dependent on IL-4, or modified by NAC. In the likely event that CD30 and its soluble counterpart prove to contribute to the pathogenesis in Th2 related diseases such as allergy, NAC may be considered as a future therapeutic agent in the treatment of these diseases.
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PMID:Thiols decrease cytokine levels and down-regulate the expression of CD30 on human allergen-specific T helper (Th) 0 and Th2 cells. 1129 19

We studied the immunomodulatory effects of royal jelly (RJ), the principal food source of the queen honeybee. In this study, suppression of allergic reactions by RJ was investigated in DNP-KLH immunized mice (DNP-KLH mice). Oral administration of RJ (1 g/kg) to DNP-KLH mice significantly decreased the serum levels of antigen-specific Ig E and significantly inhibited DNP-KLH mediated-histamine release from mast cells, resulting in the suppression of immediate hypersensitivity reactions of ear skin. In DNP-KLH mice, IFN-gamma (Th1 cytokine) production from CD4+ T cells was suppressed and IL-4 (Th2 cytokine) production from CD4+ T cells was increased as compared to normal mice. On the other hand, RJ improved the balance of Th1/Th2 cell responses from Th2-dominant to Th1-dominant. RJ significantly increased GSH levels in macrophages from DNP-KLH mice. In addition, the administration of RJ to DNP-KLH mice increased IL-12 p40 mRNA expression and NO production, and decreased PG E2 production from macrophages as compared to untreated DNP-KLH mice. These results suggested that RJ suppressed antigen-specific Ig E production and histamine release from mast cells in association with the restoration of macrophage function and improvement of Th1/Th2 cell responses in DNP-KLH mice.
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PMID:Suppression of allergic reactions by royal jelly in association with the restoration of macrophage function and the improvement of Th1/Th2 cell responses. 1136 35

Interleukin-12 (IL-12) is secreted from monocytes and macrophages; it exerts pleiotropic effects on T cells and natural killer (NK) cells, and stimulates interferon-gamma (IFN-gamma) secretion. Glutathione tripeptide regulates the intracellular redox status and other aspects of cell physiology. We examined whether IFN-gamma and IL-4 affect the balance between intracellular reduced glutathione (GSH) and oxidized (GSSG) glutathione, as this may affect IL-12 production in human alveolar macrophages (AM). We used both AM from healthy non-smokers obtained by bronchoalveolar lavage and the monocytic THP-1 cell line in this study. Incubation of AM for 2 h with the GSH precursor N-acetylcysteine (NAC) increased the intracellular GSH/GSSG ratio, and enhanced lipopolysaccharide (LPS)-induced IL-12 secretion by AM. In THP-1 cells, NAC increased the GSH/GSSG ratio and the expression of LPS-induced IL-12 mRNA, whereas L-buthionine-[S,R]-sulphoximine (BSO) decreased these. NAC and BSO offset their own effects on the intracellular GSH/GSSG ratio and the expression of LPS-induced IL-12 mRNA. Furthermore, exposure of AM to the helper T cell type 1 (Th1) cytokine IFN-gamma or the helper T cell type 2 (Th2) cytokine IL-4 for 72 h increased and decreased the GSH/GSSG ratio, respectively. Lipopolysaccharide (LPS)-induced secretion of IL-12 in AM was enhanced by IFN-gamma but inhibited by IL-4. These results suggest that IFN-gamma and IL-4 oppositely affect the GSH/GSSG balance, which may regulate IL-12 secretion from AM in response to LPS.
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PMID:Regulation of LPS induced IL-12 production by IFN-gamma and IL-4 through intracellular glutathione status in human alveolar macrophages. 1142 7

We have been proposing the functional distinction of two classes of macrophages (Mp), namely the reductive macrophages (RMp) with high intracellular content of glutathione (GSH) and the oxidative macrophages (OMp) with reduced content. At the same time we have been investigating the variation of RMp/OMp balance during aging of mice, especially in relation to the age related onset of autoimmune diseases. In this paper we have investigated the Th1/Th2 balance of thioredoxin (TRX) transgenic (Tg) mice, with prolonged life longevity, during aging in the context of the intracellular redox status of Mp, which has been hypothesized to be crucial in regulating the Th1/Th2 balance. It was confirmed that peritoneal resident Mp of Tg mice showed the higher GSH/GSSG ratios compared with that of age matched wild type (WT) mice. The predominance of RMp was associated with the sustained maintenance of Th1 prevalence during aging until 2 years in Tg mice, whereas WT littermates showed rapid polarization to Th2 around the age of 8 months. The Tg mice showed elevation of IFN-gamma and reduction of IL-10 with moderate change of IL-4 produced by CD4+ T cells. The WT mice showed inverse changes of IFN-gamma/IL-4 and IFN-gamma/IL-10 ratios during aging. In addition, IL-10 production by Mp was dramatically reduced in aged Tg mice. Thus, TRX Tg mice may be useful to investigate the contribution of the anti-oxidant defense mechanism during aging accompanied with increasing oxidative stress.
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PMID:Intracellular thiol redox status of macrophages directs the Th1 skewing in thioredoxin transgenic mice during aging. 1184 34

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