Vitamin C enters mouse T cells as dehydroascorbic acid in vitro and does not recapitulate in vivo vitamin C effects

Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-799, Republic of Korea.
Immunobiology (Impact Factor: 3.04). 02/2009; 214(4):311-20. DOI: 10.1016/j.imbio.2008.09.003
Source: PubMed


Vitamin C is an essential micronutrient, which has been implicated in various biological processes, including immune response. In fact, in vivo administration of vitamin C modulates T cell proliferation and cytokine secretion. In this study, we analyzed the mechanism by which mouse T cells take up vitamin C, and whether this uptake directly affected T cell functions. T cells internalized more vitamin C when they were activated, due to enhanced glucose transporter (GLUT)-1 and GLUT-3 expression that persisted up to 48 h after activation. Blocking oxidation of ascorbic acid (the reduced form of vitamin C) in the culture medium with 1,4-dithio-threitol (DTT) almost completely inhibited the enhanced vitamin C uptake. The presence of vitamin C at low concentrations during in vitro T cell activation did not affect proliferation or cytokine secretion (IFN-gamma, TNF-alpha, or IL-4) in response to PMA/ionomycin. In contrast, high concentrations (0.25-0.5 mM) of vitamin C lowered cell viability, reduced thymidine uptake, and decreased cytokine secretion. In conclusion, activated T cells upregulated GLUT-1 and -3 to increase vitamin C uptake. They took up vitamin C mostly in its oxidized form, rarely in its reduced form. Application of vitamin C to T cells in vitro did not recapitulate previously reported in vivo responses to vitamin C, suggesting that in vivo, vitamin C modulates T cells indirectly through other components of the microenvironment.

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    • "It could be possible that vitamin C may act directly on T cells, which then influence isotype switching in B cells. However, it does not seem to be the case, based on our recent results (Maeng et al., 2009), in which in vitro treatment of vitamin C did not induce any changes with respect to Th1/Th2 polarization. Alternately, it is possible that vitamin C directly acts on dendritic cells, which in turn affect T cells, to modulate isotype switching. "
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    ABSTRACT: Vitamin C, one of essential micronutrients, has been reported to modulate the humoral immune responses in some mammals. We investigated whether vitamin C might modulate this response in mice by directly affecting B cells. Splenic B cells were isolated and activated by CD40- and B cell receptor-ligation in vitro. The cells were cultured with a pretreatment of vitamin C from 0 to 1 mM of concentrations. Vitamin C slightly increased apoptosis of B cells dose-dependently and behaved as an antioxidant. We found that in vivo administration of vitamin C by intraperitoneal injection affected isotype switching as previously reported: the titer of antigen-specific IgG1 antibody was decreased, while that of IgG2a was unaffected. Somewhat different from those observed in vivo, in vitro exposure to vitamin C slightly decreased isotype switching to IgG1 and increased isotype switching to IgG2a. Pretreatment with vitamin C in the safe range did not affect either proliferation of cultured B cells or the expression of CD80 and CD86 in those cells. Taken together, in vivo results suggest that vitamin C acts to modulate isotype switching in the mouse. However, because of our in vitro results, we suggest that the modulation exerted by vitamin C in vivo is by indirectly affecting B cells, perhaps by directly influencing other immune cells such as dendritic cells.
    Anatomy & cell biology 03/2010; 43(1):25-35. DOI:10.5115/acb.2010.43.1.25
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    ABSTRACT: Background: Bronchial asthma is a disease characterized by paroxysmal and reversible obstruction of the airways. The imbalance between the oxidant and antioxidant system that is called oxidative stress is critical in asthma pathogenesis. It is likely, therefore, that antioxidants may be effective in the treatment of asthma. Systemic treatment with glucocorticoids has been reported to inhibit smooth muscle hypercontraction which may account partially for their beneficial effects in the treatment of asthma. Objective: The present study was conducted in order to study the effect of dexamethasone and some antioxidant vitamins on interleukin-4 (IL-4), immunoglobulin E (IgE) and heat shock protein 70 (Hsp70) in bronchial asthma in rats, and to recognize their possible beneficial role. Method: The study was conducted on 60 adult male albino rats randomly divided into 4 groups (15 for each group): including normal control group (group A); asthma model group where rats were sensitized by ovalbumin and challenged with antigen aerosol producing bronchial asthma (group B); asthma model group treated with antioxidant vitamins (vitamin E and vitamin C) (group C); asthma model group treated with dexamethasone (group D). Blood and lung samples were collected from all groups. Results and Conclusion: Our results revealed a significant decrease of serum reduced glutathione (GSH) levels among groups B, C and D as compared to group A, while there was a significant increase in group C and D as compared to group B. Antioxidant and dexametha-sone treatment resulted in a significant decrease of serum IL-4, malondialdehyde (MDA), and serum IgE levels in group C and D as compared to group B. Antioxidant treatment resulted in a significant decrease of serum Hsp70 level as compared to group B, while dexamethasone treatment resulted in a significant increase of serum Hsp70 level as compared to group B. This study suggests that it is likely that a combination of antioxidant vitamins may be effective in the treatment of asthma, considering their reported effects on lowering MDA, IL-4, and IgE levels, and the similar beneficial effects of dexamethasone in addition to increasing the expression of Hsp70 in the studied model of bronchial asthma.
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    ABSTRACT: Vitamin C has been reported to shift immune responses toward Th1. In this study, we evaluated whether this effect was by way of dendritic cells. Murine dendritic cells (DCs) were prepared from bone marrow precursors. DCs treated with vitamin C secreted an increased amount of IL-12p70 after activation with LPS. These cells rendered naïve T cells to secrete more Th1 cytokine, IFN-γ, and less Th2-cytokine, IL-5 in the culture supernatants. Vitamin C-treatment also increased phosphorylation of p38 and ERK1/2 in DCs. p38 inhibitor in culture media suppressed the effect of vitamin C to elevate IL-12p70 secretion. In contrast, ERK inhibitor elevated IL-12p70 secretion. In summary, vitamin C taken up into DCs increased IL-12p70 secretion of these cells by modulating the activation of signal molecules, and thus shifted immune responses toward Th1. These data provide us a new insight on the role of vitamin C in modulating immune responses.
    Cellular Immunology 10/2010; 266(2):192-9. DOI:10.1016/j.cellimm.2010.10.005 · 1.92 Impact Factor
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