Effects of supplementation with tocotrienol-rich fraction on immune response to tetanus toxoid immunization in normal healthy volunteers

Mahalingam, Dashayini; Radhakrishnan, Ammu Kutty; Amom, Zulkhairi; Ibrahim, Nurjahan Mohd; Nesaretnam, Kalanithi

doi:10.1038/ejcn.2010.184

Cited by 54 publications

(44 citation statements)

References 23 publications

(24 reference statements)

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“…For instance, γ-tocotrienol (γTE), a natural form of vitamin E rich in palm oil, has been reported to inhibit NF-κB activation in leukemia KBM-5 and other cancer cells (12) as well as macrophages (13, 14). Consistently, γTE supplementation inhibits proinflammatory cytokines in animals and human subjects (15, 16). Despite these interesting results, the molecular mechanism responsible for the anti-NF-κB effect has not been identified.…”

Section: Introductionmentioning

confidence: 82%

“…In addition, A20 has been recognized as a tumor suppressor in lymphomas as A20 was inactivated in many lymphomas and reintroduction of A20 promoted apoptosis and growth arrest of cancer cells (4). Given that NF-κB target genes regulate cell proliferation, cytokines and survival, the induction of A20 and consequent inhibition of NF-κB by γTE likely contributes to its antiproliferative, proapoptotic, anti-inflammatory and immunomodulatory effects (12, 15, 16, 28). …”

Section: Discussionmentioning

confidence: 99%

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Vitamin E γ-Tocotrienol Inhibits Cytokine-Stimulated NF-κB Activation by Induction of Anti-Inflammatory A20 via Stress Adaptive Response Due to Modulation of Sphingolipids

Wang

Park

Jang

et al. 2015

The Journal of Immunology

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Nuclear factor-κB (NF-κB) plays a central role in pathogenesis of inflammation and cancer. Many phytochemicals including gamma-tocotrienol (γTE), a natural form of vitamin E, have been shown to inhibit NF-κB activation, but the underlying mechanism has not been identified. Here we show that γTE inhibited cytokine-triggered activation of NF-κB and its upstream regulator TGFβ-activated kinase-1 in murine RAW264.7 macrophages and primary bone marrow-derived macrophages. In these cells, γTE induced up-regulation of A20, an inhibitor of NF-κB. Knockout of A20 partially diminished γTE’s anti-NF-κB effect but γTE increased another NF-κB inhibitor Cezanne in A20−/− cells. In search of the reason for A20 upregulation, we found that γTE treatment increased phosphorylation of translation initiation factor 2 (eIF2α), IκBα and JNK, indicating induction of endoplasmic reticulum (ER) stress. LC-MS/MS analyses revealed that γTE modulated sphingolipids including enhancement of intracellular dihydroceramides, sphingoid bases in de novo synthesis of sphingolipid pathway. Chemical inhibition of de novo sphingolipid synthesis partially reversed γTE’s induction of A20 and anti-NF-κB effect. The importance of dihydroceramide increase is further supported by the observation that C8-dihydroceramide mimicked γTE in up-regulating A20, enhancing ER stress and attenuating TNF-triggered NF-κB activation. Our study identifies a novel anti-NF-κB mechanism where A20 is induced by stress-induced adaptive response as a result of modulation of sphingolipids, and demonstrates an immune-modulatory role of dihydrocermides.

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Section: Introductionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Vitamin E γ-Tocotrienol Inhibits Cytokine-Stimulated NF-κB Activation by Induction of Anti-Inflammatory A20 via Stress Adaptive Response Due to Modulation of Sphingolipids

Wang

Park

Jang

et al. 2015

The Journal of Immunology

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“…In contrast, some randomized trials have found a positive effect of vitamin E supplementation on vaccine responses. A randomized trial conducted among healthy Malaysian women aged 18 to 25 determined that vitamin E significantly increased anti-tetanus antibody titers following revaccination compared to placebo (31). A trial conducted in healthy U.S. elderly subjects also found that highdose vitamin E supplementation increased anti-tetanus titers and antibody responses to hepatitis B following vaccination, but there was no effect on diphtheria or pneumococcal polysaccharide vaccine responses (32).…”

Section: Discussionmentioning

confidence: 99%

Effect of Multivitamin Supplementation on Measles Vaccine Response among HIV-Exposed Uninfected Tanzanian Infants

Sudfeld

Duggan

Histed

et al. 2013

Clin Vaccine Immunol

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Immunization and nutritional interventions are mainstays of child health programs in sub-Saharan Africa, yet few published data exist on their interactions. HIV-exposed (but uninfected) infants enrolled in a randomized placebo-controlled trial of multivitamin supplements (vitamins B complex, C, and E) conducted in Tanzania were sampled for an assessment of measles IgG quantity and avidity at 15 to 18 months. Infants were vaccinated between 8.5 and 12 months of age, and all mothers received high-dose multivitamins as the standard of care. Of 201 HIV-exposed infants who were enrolled, 138 (68.7%) were seropositive for measles. There were no effects of infant multivitamin supplementation on measles seroconversion proportions, IgG concentrations, or IgG avidity (P > 0.05). The measles seroconversion proportion was greater for HIV-exposed infants vaccinated at 10 to 11 months of age than for those vaccinated at 8.5 to 10 months (P ‫؍‬ 0.032) and greater for infants whose mothers had a CD4 T-cell count of <200 cells/l than for infants whose mothers had a CD4 T-cell count of >350 cells/l (P ‫؍‬ 0.039). Stunted infants had a significantly decreased IgG quantity compared to nonstunted infants (P ‫؍‬ 0.012). As for measles avidity, HIV-exposed infants vaccinated at 10 to 11 months had increased antibody avidity compared to those vaccinated at 8.5 to 10 months (P ‫؍‬ 0.031). Maternal CD4 T-cell counts of <200 cells/l were associated with decreased avidity compared to counts of >350 cells/l (P ‫؍‬ 0.047), as were lower infant height-for-age z-scores (P ‫؍‬ 0.016). Supplementation with multivitamins containing B complex, C, and E does not appear to improve measles vaccine responses for HIV-exposed infants. Studies are needed to better characterize the impact of maternal HIV disease severity on the immune system development of HIV-exposed infants and the effect of malnutrition interventions on vaccine responses. (This study has been registered at ClinicalTrials.gov under registration no. NCT00197730.)

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“…In a double-blinded, placebo-controlled clinical trial, healthy volunteers supplemented with 400mg of tocotrienol-rich fraction had increased production of anti-tetanus toxoid antibody, IL-4 and interferon-gamma induced by tetanus toxoid vaccine challenge but reduced IL-6, compared with placebos [144]. A topical formulation containing tocopherols and tocotrienols showed photoprotective effect in photosensitive subjects [145].…”

Section: Health Benefits In Human Clinical Studiesmentioning

confidence: 99%

Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

Jiang

2014

Free Radical Biology and Medicine

723

579

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The Vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol (αT) is the predominant form of vitamin E in tissues and its deficiency leads to ataxia in humans. However, results from many clinical studies do not support protective roles of αT in disease prevention in people with adequate nutrient status. On the other hand, recent mechanistic studies indicate that other forms of vitamin E such as γ-tocopherol (γT), δ-tocopherol (δT) and γ-tocotrienol (γTE) have unique antioxidant and anti-inflammatory properties that are superior to αT in prevention and therapy against chronic diseases. These vitamin E forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids and suppress pro-inflammatory signaling such as NF-κB and STAT3/6. Unlike αT, other vitamin E forms are significantly metabolized to carboxychromanols via cytochrome P-450 (CYP4F2)-initiated side-chain ω-oxidation. Long-chain carboxychromanols, esp.13’-carboxychromanols, are shown to have stronger anti-inflammatory effects than un-metabolized vitamins and may therefore contribute to beneficial effects of vitamin E forms in vivo. Consistent with mechanistic findings, animal and human studies show that γT and tocotrienols may be useful against inflammation-associated diseases. This review focuses on non-αT forms of vitamin E with respect to their metabolism, anti-inflammatory effects and mechanisms and in vivo efficacy in preclinical models as well as human clinical intervention studies.

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Effects of supplementation with tocotrienol-rich fraction on immune response to tetanus toxoid immunization in normal healthy volunteers

Cited by 54 publications

References 23 publications

Vitamin E γ-Tocotrienol Inhibits Cytokine-Stimulated NF-κB Activation by Induction of Anti-Inflammatory A20 via Stress Adaptive Response Due to Modulation of Sphingolipids

Vitamin E γ-Tocotrienol Inhibits Cytokine-Stimulated NF-κB Activation by Induction of Anti-Inflammatory A20 via Stress Adaptive Response Due to Modulation of Sphingolipids

Effect of Multivitamin Supplementation on Measles Vaccine Response among HIV-Exposed Uninfected Tanzanian Infants

Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

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