Regulatory role of vitamin E in the immune system and inflammation

Abstract

Vitamin E, a potent lipid-soluble antioxidant, found in higher concentration in immune cells compared to other cells in blood, is one of the most effective nutrients known to modulate immune function. Vitamin E deficiency has been demonstrated to impair normal functions of the immune system in animals and humans, which can be corrected by vitamin E repletion. Although deficiency is rare, vitamin E supplementation above current dietary recommendations has been shown to enhance the function of the immune system and reduce risk of infection, particularly in older individuals. The mechanisms responsible for the effect of vitamin E on the immune system and inflammation have been explored in cell-based, pre-clinical and clinical intervention studies. Vitamin E modulates T cell function through directly impacting T cell membrane integrity, signal transduction, and cell division, and also indirectly by affecting inflammatory mediators generated from other immune cells. Modulation of immune function by vitamin E has clinical relevance as it affects host susceptibility to infectious diseases such as respiratory infections, in addition to allergic diseases such as asthma. Studies examining the role of vitamin E on the immune system have typically focused on α-tocopherol; however emerging evidence suggests that other forms of vitamin E, including other tocopherols as well as tocotrienols, may also have potent immunomodulatory functions. Future research should continue to identify and confirm the optimal doses for individuals at different life stage, health condition, nutritional status, and genetic heterogeneity. Future research should also characterize the effects of non-tocopherol vitamin E on immune cell function as well as their potential clinical application.

Introduction

The immune system plays a critical role in the body, mainly serving as a defense against infectious agents, response to injury, and identification and elimination of tumor cells [1]. Appropriate and effective immune responses are necessary for distinguishing “self” such as dietary antigens and commensal bacteria and “non-self” including viruses, bacteria, parasites and fungi. The innate and acquired (also called adaptive) immune systems are well coordinated in their functions for the protection of the host. The innate immune system serves as the first line of defense against foreign antigens. The cells of the innate immune system, including monocytes/macrophages, neutrophils, natural killer (NK) cells, dendritic cells and granulocytes, play a critical role in directly attacking invading pathogens and facilitating activation of the adaptive immune system. The acquired immune system, comprised of T and B cells, recognizes foreign pathogens presented by antigen presenting cells (dendritic cells, macrophages, and B cells) and mounts a more efficient and specific response to pathogens, as well as developing immunological memory.

Under normal conditions, the immune system acts acutely for which temporary action occurs against invading pathogens. This inflammatory response is an essential component of the immune system and involves coordination among different immune cells, cytokines, and other signaling molecules. However, when the activation of the immune system is prolonged and unresolved, inflammation persists, resulting in a situation known as chronic, low grade inflammation. Chronic, low grade inflammation is a common feature of many chronic metabolic conditions including obesity, non-alcoholic fatty liver disease and type 2 diabetes [2,3], and is also associated with aging. In aged individuals, this chronic inflammatory state is confounded by impaired defense-related immune responses, in particular cell mediated functions, as well as a variety of alterations in systemic factors such as hormonal and metabolic changes which have been reviewed previously [4,5]. It is well-known that nutritional status is important for maintaining normal functions of the immune system and preventing or mitigating the dysfunction induced by internal or external factors. Nutritional deficiencies often result in impaired function, and conversely, intakes at recommended or above recommended levels can resume or further enhance functions of the immune system.

Vitamin E is one of the most effective nutrients known to modulate immune function. This is in part due to its protective effect against oxidation of polyunsaturated fatty acids which are enriched in membranes of immune cells, making them prone to oxidative damage resulting from their high metabolic activity and normal defense against pathogens [6,7]. Vitamin E deficiency and supplementation have been demonstrated to affect the immune system and inflammation through various regulatory roles including alterations in membrane integrity and signal transduction, modulation of inflammatory mediators and cell cycle. Modulation of immune function by vitamin E has clinical relevance as it affects host susceptibility to bacterial and viral infection, as reviewed previously [8–10].

Vitamin E and immune functions

Animal and human studies have demonstrated that vitamin E deficiency impairs both humoral (antibody production) and cell-mediated (particularly that of T cells) immune functions (reviewed by Han and Meydani [11]). Lower antibody production in mice [12] and rats [13] and impaired lymphocyte proliferation in rats [14], dogs [15], lambs [16], pigs [17], and chickens [18] have been reported as a consequence of vitamin E deficiency which can be reversed by repletion of vitamin E. In humans, vitamin E deficiency is very rare, but limited number of studies examining vitamin E deficiency in humans supports the essential role of vitamin E in immune function. A case report of vitamin E deficiency as a result of an intestinal malabsorption disorder demonstrated impaired delayed-type hypersensitivity (DTH), an in vivo measure of cell-mediated immune function, and impaired ex vivo T cell function assessed by interleukin (IL)-2 production, a key cytokine essential for T cell function. A reduction in inflammatory cytokines and improvement in T cell proliferation with vitamin E supplementation was also observed [19]. Similarly, neutrophils from vitamin E deficient preterm infants showed impaired bactericidal activity and phagocytic capacity [20].

While vitamin E deficiency impairs immune function, there is evidence from both animal and human studies that vitamin E supplementation, above current dietary recommendations, enhances the function of the immune system. In animals, vitamin E supplementation improves T cell mediated functions including thymic T cell differentiation [21], lymphocyte proliferation [22–27], IL-2 production [22,24] and helper T cell activity [22,24]. Innate immune functions including NK cell activity and macrophage phagocytic capacity are also enhanced by vitamin E supplementation [26]. Vitamin E supplementation appears particularly effective in improving age-associated deteriorations of immune and inflammatory responses which have been reviewed previously [9–11]. Most notably, vitamin E supplementation (500 ppm dl-α-tocopheryl acetate) in old mice improved T cell mediated responses, including lymphocyte proliferation, IL-2 production and DTH response to levels comparable to those in young mice [22]. Evidence in humans also supports the role of vitamin E in enhancing innate and adaptive immune responses. Vitamin E supplementation increased leukocyte phagocytic capacity [28] but decreased bactericidal activity [28,29], believed to be related to the antioxidant function of vitamin E and reduced production of hydrogen peroxide. In elderly subjects, the declined functions of neutrophils and NK cells were improved with vitamin E supplementation to the levels comparable to those in adult controls [30]. Several double-blinded, placebo controlled clinical trials have demonstrated the efficacy of vitamin E in improving T-cell-mediated functions in older adults. Supplementation of 800 IU/day vitamin E (dl-α-tocopheryl acetate) for one month to healthy older adults (≥ 60 years old) improved in vivo and ex vivo indices of T cell mediated functions [31]. A subsequent trial demonstrated that 200 IU/d vitamin E (dl-α-tocopherol) was optimal compared to doses of 60 and 800 IU/d in improving vaccine efficacy to tetanus and hepatitis B as well as DTH response [32]. A study conducted by De la Fuente et al. [30] supported the efficacy of 200 IU vitamin E (dl-α-tocopherol) in enhancement of T cell function in older adults.

Mode of action for vitamin E’s immunoregulatory effects

The mechanisms responsible for the immunomodulatory effects of vitamin E have been explored in cell-based, animal, and human studies. Vitamin E has both direct and indirect effects on immune cells, with most evidence obtained from studies focused on the effects on T cell function. It is generally recognized that, similar to the effects on other cells, the scavenging of reactive oxygen species and reduction of oxidative stress play a key role in vitamin E’s effects on the immune system. Membrane integrity, inflammation, signal transduction, and cell cycle division are all processes that are sensitive to oxidative stress.

1). Direct effects: alterations of membrane integrity and signaling

As mentioned above, immune cells are particularly enriched in vitamin E, likely to protect high membrane content of polyunsaturated fatty against oxidative damage produced as a result of their high metabolic activity and their normal defensive function [6,7]. Immune cells are highly dependent on cell membrane composition and structure as their membranes are a primary site where external signals are translated through different signal transduction mechanism to plasma and nucleus to modulate key regulatory genes. By preventing lipid peroxidation and the associated cell membrane damage, vitamin E may assist in the maintenance of membrane integrity, maintain signal transduction and production of key proteins and other mediators and directly affect the function of immune cells. Additionally, vitamin E may directly modulate certain properties of cell membranes, including lipid raft mobility, which may influence movement and activation of surface signaling molecules as reviewed previously [33].

Modulation of cell membrane integrity may result in alteration of signal transduction ultimately leading to functional changes, specifically in T cells. The direct effects of vitamin E on alterations of membrane integrity and signaling have been demonstrated in both in vitro and in vivo models. Isolated splenic naïve T cells from old mice had a significantly lower ability to divide and produce IL-2 compared to T cells from young mice. In vitro supplementation of vitamin E (46 µmol/L of d-α-tocopherol), comparable to plasma concentrations of vitamin E in humans consuming 200 IU d-α-tocopherol/d, was shown to improve these age-associated declines. These improvements in age-associated impairments of T cell function were only observed in naïve T cells, but not in memory T cells [34]. This corresponds with reports that naïve T cells are more susceptible to oxidative damage [35]. It is thought that these effects may be mediated through the effect of vitamin E on early events in T cell activation. Studies indicate that vitamin E may enhance early events in T cell activation including the formation of synapses between naïve helper (CD4+) T cells and antigen presenting cells [36]. The enhancement of naïve T cell function by vitamin E was also attributed to redistribution of membrane associated key signaling molecules including linker for activation of T cells family member 1 (LAT), tyrosine-protein kinase ZAP70 (ZAP70), phospholipase-Cγ and Vav proteins [36]. Alterations in immune cell signaling are particularly relevant for older animals and humans as there is an age-associated decline in effective synapse formation, with the naïve CD4+ T cell subset representing the most vulnerable population to these defects.

2). Indirect effects: suppression of inflammatory factors

Vitamin E exerts indirect regulatory effects on T cells through modulation of inflammatory mediators such as pro-inflammatory cytokines and prostaglandin E₂ (PGE₂), a lipid mediator. The effect of vitamin E in modulation of PGE₂ production by macrophages has been reviewed previously [9,37]. Briefly, PGE₂ activates adenylyl cyclase to increase cyclic adenosine monophosphate (cAMP) levels leading to suppressed T cell response [38,39]. PGE₂ affects both the innate and adaptive immune system [40–43], including inhibition of T cell proliferation, IL-2 receptor expression and IL-2 production [41]. The T cell suppressive effects of PGE₂ involve inhibition of several early signaling events that occur after T cell activation [43]. Although the mechanism by which vitamin E inhibits PGE₂ production is not yet fully understood, studies have shown that supplementation of vitamin E (500 mg/kg for 30 days) reduced PGE₂ production by inhibiting enzymatic activity of cyclooxygenase 2 (COX-2), a rate limiting enzyme involved in the conversation of arachidonic acid to prostaglandins [44, 45]. Interestingly, vitamin E supplementation did not affect mRNA or protein expression of COX-1 or COX-2 [45–47]. This suggests that vitamin E’s regulation of COX-2 enzymatic activity occurs at the post-translational levels. Toward this end, studies indicate that inhibition of COX-2 activity by vitamin E may be mediated by reactive oxygen species peroxynitrite, at least in old mice [48].

In addition to the suppression of PGE₂, vitamin E supplementation in the aged has been shown to reduce production of other inflammatory markers including tumor-necrosis factor (TNF)-α, and IL-6, particularly in response to pathogens [45,49,50]. Old mice infected with influenza A/Port Chalmers/1/27 (H3N2) had impaired production of T helper 1 (Th1) cytokines IL-2 and interferon (IFN)-γ, and higher lung viral titers [44,49] compared to young mice. Vitamin E supplementation (500 mg/kg) for 30 days enhanced the Th1 response that is generally impaired in the aged. This suggests that enhancement of Th1 response may be a central mechanism whereby vitamin E improves response to influenza infection. Vitamin E has also been demonstrated to play a role in production of cytokines. Consistent with models of respiratory infection, vitamin E supplementation in healthy mice (4–6 weeks) promotes Th1 response, by increasing production of IFN-γ and decreasing production of pro-inflammatory cytokine TNF-α [51]. In LPS-stimulated peripheral blood mononuclear cells (PBMCs), vitamin E supplementation appears to reduce the inflammatory response by reducing pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α from monocytes [52]. Similar to the alterations of PGE₂, the effect of vitamin E on pro-inflammatory cytokines appears to also be mediated through stimulation of cAMP [52].

Clinical relevance of vitamin E in the regulation of immune function

Evidence from animal and human studies has demonstrated that the immunoregulatory role of vitamin E is associated with reducing risk for infectious diseases such as respiratory infections, as well as some allergic diseases such as asthma. Respiratory infections, such as Streptococcus pneumonia and influenza, are particularly problematic for older adults as they are more susceptible to these infections, have longer recovery periods from infection and as a result have higher rates of hospitalization, morbidity, and mortality [53–55]. Due to the vulnerabilities faced by older adults, both animal and human studies have focused on the potential for enhanced immune function by vitamin E supplementation in response to respiratory infections.

1). Pneumonia

It has been reported that old mice are more susceptible to S. pneumonia infection, and have greater lung inflammation, neutrophil infiltration, and pulmonary bacterial burden, compared to young animals. This increased susceptibility to infection was reduced by vitamin E supplementation (500 mg/kg for 4 weeks) [50]. Vitamin E was effective in reducing neutrophil migration and production of inflammatory cytokines which was associated with reduced lethal septicemia in older mice [50]. This suggests that vitamin E is capable of modulating the innate immune response to bacterial pneumonia infection and there may be an age-specific requirement for vitamin E in order to maintain optimal immune response.

In older adults, self-reported vitamin E supplementation was associated with a 63% lower rate of re-hospitalization within 90 days among those previously hospitalized with pneumonia [56]. In a retrospective cohort of healthy older adults (≥60 y), plasma vitamin E levels was negatively correlated with the number of past infections, yet there was no correlation between vitamin E status and measurements of T cell immune function including phenotypes, proliferation, and DTH response [57]. In a randomized placebo controlled trial of vitamin E supplementation (60, 200, or 800 mg/d) for 235 days in healthy elderly, there was a non-significant (p<0.09) 30% lower incidence of self-reported infections compared to those receiving the placebo [32]. In a larger, double-blind, placebo-controlled trial, it was found that vitamin E supplementation (200 mg/d) for one year in elderly nursing home residents (>65 y) resulted in lower incidence and shorter duration of upper respiratory infection, particularly the common cold, compared to those receiving the placebo [58]. Yet, not all human studies support the efficacy of vitamin E supplementation in modulation of clinically relevant immunological outcomes. A study of vitamin E supplementation (200 IU/d) in Dutch older adults (≥60 years old) found no significant effect of vitamin E on respiratory infections [59]. In a secondary analysis of male Finnish smokers participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC study), vitamin E supplementation was found to affect pneumonia risk, but the effects varied depending on the characteristics of the participants [60,61]. For example, vitamin E supplementation appeared to reduce the risk of pneumonia only in older subjects over 60–65 years old [60]. The effect of vitamin E supplementation on common cold risk was also largely influenced by the age of subjects (after about age 65) in addition to smoking status and living in urban or rural areas [61]. The variable effectiveness of vitamin E interventions may be attributed to the differences in the population of study and vitamin E administration. Genetic background has been identified as an important non-modifiable factor in both the bioavailability and cellular activity of vitamin E, which has been reviewed previously [62]. Polymorphisms in genes related to vitamin E metabolism including apolipoprotein E, lipoprotein lipase, CD36 scavenger receptor, scavenger receptor class B type I, and α-tocopherol transfer protein may influence the effect of vitamin E supplementation. Thus far, there has been limited investigation regarding the gene-vitamin E interaction. Belisle et al. [63] demonstrated that in elderly subjects supplemented with vitamin E, those with the A/A and A/G genotype at the TNF-α−308G>A had lower TNF-α production compared to subjects receiving the placebo with the same genotype [63]. An A allele in TNF-α−308G>A has been shown to be associated with higher TNF-α levels [64], suggesting that vitamin E may be most effective at reducing pro-inflammatory cytokines in those genetically predisposed to elevated inflammation.

2). Influenza

Similar to pneumonia infection, old mice are more susceptible to influenza infection, experiencing greater weight loss and mortality [65,66], impaired production of Th1 cytokines IL-2 and IFN-γ, and higher lung viral titers after infection with influenza A/Port Chalmers/1/27 (H3N2) [49,67] compared to young mice. Vitamin E supplementation (500 mg/kg diet) for 30 days enhanced Th1 response and improved lung pathology, weight loss, and mortality following influenza infection in old mice.

3). Asthma

In addition to infections in the respiratory system, vitamin E may play a role in development of allergic airway diseases such as asthma and wheeze across life stages. Several prospective cohort studies have examined the association between maternal vitamin E intake (both dietary and supplemental sources) during pregnancy and infant asthma and allergy development. Maternal vitamin E intake during pregnancy was negatively associated with various wheezing outcomes including recurrent wheezing, any wheezing [68] and wheeze in the absence of a cold [69] in children at 2 years of age. Intake of vitamin E from supplements was more strongly associated with wheezing outcomes compared to dietary sources [68]. In a follow up to the study by Martindale et al. [69], researchers examined if the association between maternal vitamin E intake and wheeze at 2 years of age persisted with age, when the asthma phenotype was better characterized [70]. In 5 year old children, wheeze and asthma outcomes were negatively associated with maternal vitamin E intake at 32 weeks of gestation, with children from mothers in the lowest quintile of vitamin E intake 3.47 times more likely to have a persistent wheezing phenotype than children from mothers with the highest quintile of vitamin E intake [70]. In children, vitamin E serum levels also appeared to be associated with asthma incidence. A case-control study found that children with bronchial asthma had significantly lower serum vitamin E concentrations compared to control children without asthma [71]. Studies in two birth cohorts that examined association between vitamin E and infant asthma and wheezing further explored the potential mechanisms for the protective effect of maternal vitamin E by showing that low vitamin E in pregnancy was associated with increased in vitro proliferative response to allergens by cord blood mononuclear cells (CBMC) [68,72].

Although there appears to be a connection between maternal vitamin E status and childhood asthma, the relationship between vitamin E and adult onset asthma or wheeze is much less clear. Troisi et al. [73] found that women consuming the highest quintile of vitamin E (median of 6.9 mg/d) had a lower 10-year incidence of asthma compared to women consuming the lowest quintile of vitamin E (3.2 mg/d). Yet, when examining both dietary and supplemental sources of vitamin E, there was no association between high and low intake and asthma incidence observed [73]. A systematic review and meta-analysis reported that both dietary vitamin E intake and serum vitamin E levels were largely unrelated to asthma incidence in adults [74]. However, when the severity of asthma was further examined, significantly lower intakes of vitamin E was seen in patients with severe asthma compared to those with mild asthma, suggesting the severity of asthma is an important outcome to consider when examining the association between vitamin E and asthma incidence. No significant difference was found in dietary intake of vitamin E in people with wheeze or risk of airway reactivity compared to those without [74]. Moreover, there was no significant difference in mean serum vitamin E concentrations observed with asthma or wheeze [74] suggesting that dietary intake of vitamin E may have greater influence regarding asthma risk than serum levels. In a parallel group randomized placebo controlled trial conducted in adults with asthma, supplementation with 500 mg α-tocopherol for 6 weeks did not alter bronchial hyperresponsiveness, nor did it cause any change in outcome measurements including asthma control and serum immunoglobulin levels compared to the placebo [75].

It appears that the association between asthma and vitamin E status, determined by dietary intake or serum concentrations, may be dependent on the life stage examined, severity of condition and outcome measures. Animal models of asthma and airway inflammation indicate that the varying results may also be due to the differential effects between various forms of vitamin E, e.g., α-tocopherol and γ-tocopherol differentially affect lung inflammation. Studies by Berdnikovs et al. [76] and McCary et al. [77] showed that in animal models of asthma and lung inflammation, α-tocopherol supplementation reduced measures of inflammation including leukocyte recruitment and endothelial cell adhesion. The opposite effect was observed with supplementation of γ-tocopherol in the same model of asthma for which leukocyte recruitment to the lung increased, resulting in increased disease severity. It is thought that the opposing actions of different forms of vitamin E are a result of the contrasting actions on endothelial cells and alterations of adhesion molecule signaling [76].

Immunoregulatory roles of non-α-tocopherol vitamin E

While the majority of research on the immunoregulatory roles of vitamin E has focused on α-tocopherol, there is emerging evidence suggesting that other forms of vitamin E, including other tocopherols and tocotrienols, may also have immunomodulatory properties [78,79].

1). Other forms of tocopherols

The focus on α-tocopherol is not surprising as this form of vitamin E is the most abundant in both diet and the body, and the most biologically active [80,81]; accordingly, it is the form for which dietary recommendations are based [82]. The other forms, including γ-, β- and δ-tocopherols, are much lower in human plasma, thus there has been limited investigation regarding their potential roles on immune function. An in vitro study [83] examined the effect of supplementation of tocopherol homologues (α-, β-, γ-, and δ-tocopherols) on murine splenocytes and observed differential effects on lymphocyte proliferation between homologues. All forms enhanced mitogen-stimulated T lymphocyte proliferation, but α-tocopherol was the most efficient at producing maximum proliferation, followed by γ-, β- and δ-tocopherols [83]. Interestingly, at higher doses of supplementation for which α-tocopherol enhanced lymphocyte proliferation, the other tocopherol homologues inhibited lymphocyte proliferation [83]. This is consistent with other studies examining the differential effects of vitamin E forms on T cell gene transcription as well as airway inflammation mentioned above. Supplementation with either α- or γ-tocopherol for 4 weeks to old mice appeared to differentially affect gene transcription related to lymphocyte proliferation, inflammation and survival [84]. Supplementation with α-tocopherol activated genes responsible for promotion of lymphocyte proliferation and survival, while γ-tocopherol activated genes related to reduction of lymphocyte proliferation, promotion of inflammation, and induction of apoptosis [84]. It has also been observed that α- and γ-tocopherols have opposing effects on inflammation [76], with γ-tocopherol increasing lung inflammation and exacerbating disease severity in an animal model of asthma. It is believed that the differential effects between tocopherol homologues may be attributed to the cytotoxicity of other forms of tocopherol at high doses. The varied immunomodulatory effects of different forms of tocopherols are not predicted from their antioxidant capacity.

In addition to the differential effects of forms of tocopherols, there is emerging evidence that the immunoregulatory effects of α-tocopherol may be different between natural and synthetically derived forms. The majority of animal and human studies have used dl-α-tocopherol supplementation, the synthetic form of vitamin E. A study by Han et al. [85] observed differential effects on T lymphocyte gene transcription between synthetic and natural (d-α-tocopherol) forms of vitamin E. This emerging evidence suggests that further studies are needed to determine the immunomodulatory effect of forms and synthetic and natural derivatives of tocopherol.

2). Tocotrienols

Compared to tocopherols, tocotrienols are much less abundant in food and there has been limited investigation regarding their immunological properties. In rats, dietary supplementation with tocotrienols for 3 weeks altered immunoglobulin (Ig) production from both splenocytes and mesenteric lymphocytes. Tocotrienols increased IgA, IgG and IgE from both splenocytes and mesenteric lymphocytes [86]. Consistent with the anti-inflammatory activities of tocopherols, tocotrienol supplementation reduced the production of TNF-α by mitogen stimulated splenocytes [86]. Similarly in mice, Ren et al. [87] examined the effect of dietary supplementation with 0.1% Tocomin^® 50%, a mixture of natural tocotrienols (12.2% α-tocotrienol, 2% β-tocotrienol, 6.2% γ-tocotrienol and 20.1% δ-tocotrienol) and 10.7% α-tocopherol, compared to a control diet containing an equal amount of α-tocopherol, on immune function in young and old mice. Supplementation with Tocomin^® 50% increased lymphocyte proliferation in both age groups, with a greater enhancement observed in old mice [87]. There was also an improvement in IL-1β production by splenocytes of old mice and increased production of IL-1β by peritoneal macrophages in both young and old mice with Tocomin^® 50% supplementation [87]. Additionally, using in vitro supplementation with individual tocotrienols (α-tocotrienol, γ-tocotrienol, and δ-tocotrienol), Ren et al. [87] found that similar to tocopherol homologues, all forms of tocotrienols tested enhanced lymphocyte proliferation, but varied in the degree of potency, with α-tocotrienol being the most efficient at producing maximum proliferation, followed by γ- and δ-tocotrienols.

Supplementation with tocotrienols may also have clinical benefits in facilitating immune responses to antigens. Radhakrishnan et al. [51] examined the effect of either tocotrienol-rich fraction (TRF), comprised of 70% tocotrienols and 30% α-tocopherol, α-tocopherol, or δ-tocotrienol on the response to tetanus toxoid (TT) vaccine. Both TRF and δ-tocotrienol enhanced the immune response to TT immunization by enhancing the production of splenocyte IFN-γ and IL-4 [51]. The promotion of Th1 response (IFN-γ) is similar to the mechanism by which α-tocopherol has been demonstrated to improve response to influenza and pneumonia infection [49].

The efficacy of TRF in improving response to TT immunization was also examined in healthy humans [88]. In a double-blinded, placebo controlled trial, subjects who consumed 400 mg/d of TRF for 56 days and were immunized with TT vaccine had higher production of IFN-γ and IL-4 in TT-stimulated peripheral blood leukocytes (PBLs) [88]. There was also lower production of IL-6 from TT-stimulated PBLs compared with the placebo group, suggesting TRF is effective in improving the immune response to TT immunization[88]. However, when healthy adult subjects were supplemented with 200 mg/d of either TRF or α-tocopherol, there was no difference in immune function compared to placebo [89]. These data suggest that similar to α-tocopherol, immuno-enhancing effect of tocotrienols may also be more pronounced in the aged compared to young. These preliminary results from limited number of studies suggest that tocotrienols may be beneficial in maintain/improving the immune response.

Conclusions

Overall, cell based, preclinical and clinical studies provide strong evidence for the immunoregulatory role of vitamin E. Several studies have explored various mechanisms by which vitamin E may exert its effects both directly through alterations of cell membrane function and cell signaling pathways and indirectly through modulation of inflammatory mediators including production of PGE₂ and cytokines. As efforts continue to understand vitamin E’s effect on immune function, future research is needed to further elucidate the mechanisms involved. Most studies have focused on T-cell function, and modulation of Th1 response, however it is likely that vitamin E may modulate other types of immune cells culminating in improved immune response and reduced risk for immune related diseases. It is worth noting that an individual’s response to vitamin E varies depending on several factors including life stage, health condition, nutritional status, and genetic heterogeneity. Of these factors, it is repeatedly observed that vitamin E is more effective in improving age-associated immune dysfunction and boosting protective immune response to pathogenic challenges in this age group. The immunomodulatory effects of supplemental vitamin E have been shown to be beneficial in mitigating several viral, bacteria and allergic diseases such as asthma. A better understanding of the effects of vitamin E and the underlying mechanisms are important for establishing the optimal vitamin E intake in both general and targeted populations. Additionally, while the majority of studies have focused on the immunoregulatory effects of α-tocopherol, there is a growing body of literature suggesting potential role of other forms of vitamin E which warrants more in-depth investigation.

Abbreviations:

cAMP

cyclic adenosine monophosphate

CBMC

cord blood mononuclear cells

COX-2

cyclooxygenase 2

DTH

delayed-type hypersensitivity

IL

interleukin

LAT

linker for activation of T cells family member 1

NK

Natural Killer

PBMC

peripheral blood mononuclear cells

PGE₂

prostaglandin E2

TNF

tumor-necrosis factor

ZAP70

tyrosine-protein kinase ZAP70