Chapter 17

Vitamin E Isoform-Specific Functions in Allergic Inflammation and Asthma

Joan M. Cook-Mills,    Northwestern University, Chicago, IL, United States

Abstract

Asthma and allergic lung disease occur as complex environmental and genetic interactions. Epidemiological studies and randomized prevention trials have demonstrated the potential of a number of protective dietary factors for asthma, including the vitamin E isoform α-tocopherol. However, reports for vitamin E have seemingly varied outcomes regarding benefits. These seemingly varied outcomes are consistent with mechanistic studies of opposing functions of the vitamin E isoforms α-tocopherol and γ-tocopherol. Moreover, the variation in global prevalence of asthma may be explained, at least in part, by tocopherol isoforms. To clearly interpret outcomes of preclinical models and clinical studies, the studies need to include measurements of the tocopherol isoforms in the supplements, in vehicles for the supplements, and in the plasma or tissues before and after intervention. Understanding the differential regulation of inflammation by tocopherol isoforms provides a basis toward designing interventions that more effectively modulate inflammatory pathways and improve lung function in disease. Furthermore, the investigation of early life diet, in relation to childhood asthma, raises the possibility of early life dietary interventions.

Keywords

Allergy; asthma; α-tocopherol; γ-tocopherol; human models; animal models

Introduction

Asthma manifests as a heterogeneous disease that results from complex interactions of environmental and genetic factors (Martinez, 2007). The World Health Organization reported that the prevalence of asthma from 1950 to the present has increased in many countries, including those with high, intermediate, and low rates of asthma (Friebele, 1996; Vollmer et al., 1998; Bousquet et al., 2005). The marked rise in rates of asthma over a few decades and the differences in rates among countries and in migrating populations suggest an important role of the local environment, such as diet, in the development of asthma. One environmental change over the past 40 years has been an increase in the γ-tocopherol isoform of vitamin E in the diet and in infant formulas that contain soybean oil, a rich source of γ-tocopherol (Cook-Mills and McCary, 2010; Uauy et al., 1994). In a model of allergic asthma in adult mice, α-tocopherol decreases and γ-tocopherol increases allergic lung inflammation in mice. Moreover, maternal supplementation of α-tocopherol decreases and maternal supplementation of γ-tocopherol increases offspring development of allergic lung inflammation (Abdala-Valencia et al., 2014, 2016). In humans, increasing α-tocopherol levels are associated with better lung function and high plasma γ-tocopherol levels are associated with lower lung function (Berdnikovs et al., 2009; Cook-Mills and McCary, 2010; Marchese et al., 2014; McCary et al., 2011). In this chapter, we discuss the complex and opposing functions of α-tocopherol and γ-tocopherol on asthma in humans and in animal models of lung inflammation. We will discuss how the variation in global prevalence of asthma may be influenced, at least in part, by country-specific plasma γ-tocopherol concentrations.

Vitamin E Isoforms, Sources, and Functions

Vitamin E consists of natural isoforms and synthetic racemic isoforms. The eight natural isomers are D-α-, D-β-, D-γ-, and D-δ-tocopherol and D-α-, D-β-, D-γ-, and D-δ-tocotrienol (Fig. 17.1). Plants synthesize the natural isoforms from tyrosine and chlorophyll (Hunter and Cahoon, 2007). These isoforms are consumed in the diet primarily from plant lipids in food and cooking oils and in vitamin supplements. After consumption of the tocopherols, they are taken up from the intestine, transported via the lymph to the blood, and then enter the liver. Mammals do not synthesize or interconvert the tocopherol isoforms. The most abundant isoforms of vitamin E are α-tocopherol and γ-tocopherol, which differ by one methyl group on the chromanol ring (Fig. 17.1). There are 10-fold higher tissue concentrations of α-tocopherol than γ-tocopherol (Wolf, 2006) because there is preferential loading of α-tocopherol on high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles in the liver by α-tocopherol transfer protein (αTTP) and because there is a higher rate of degradation of γ-tocopherol into its metabolites for excretion (Bella et al., 2006; Leonard et al., 2005). Human genetic variants of liver α-TTP affect α-tocopherol concentrations, resulting in α-tocopherol deficiency (Cavalier et al., 1998). Moreover, αTTP is also expressed by trophoblasts, fetal endothelium, and amnion epithelium of the placenta (Muller-Schmehl et al., 2004). This localization of α-TTP is important because basal levels of α-tocopherol are required for placental development (Jishage et al., 2005; Muller-Schmehl et al., 2004). In addition, other diet components may influence tocopherol absorption, including dietary L-carnitine, which enhances absorption of α-tocopherol in rats (Zou et al., 2005). It is also reported that human plasma levels of α-tocopherol but not γ-tocopherol are increased in male adults and children by the apolipoprotein A5 1131 T>C gene polymorphism (Guardiola et al., 2010; Sundl et al., 2007). In mice, apoE4 mice have lower plasma α-tocopherol levels than do apoE3 mice (Huebbe et al., 2009). Tocopherols in plasma lipid particles are transferred to cells by plasma phospholipid transfer protein, scavenger receptors, or the lipoprotein lipase pathway. After uptake, the tocopherols are found in cell membranes because they are lipid vitamins.

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Figure 17.1 Vitamin E isoforms.

Within tissues, tocopherol isoforms have antioxidant and nonantioxidant functions. Tocopherols are antioxidants. Both α-tocopherol and γ-tocopherol at equal molar concentrations have a relatively similar capacity to scavenge reactive oxygen species (ROS) during lipid peroxidation in vitro and in cells (Nishio et al., 2013; Yoshida et al., 2007). Thus, because α-tocopherol is at a 10-fold higher concentration in tissues than γ-tocopherol, there is 10-fold more scavenging of ROS by α-tocopherol than by γ-tocopherol in vivo. Besides scavenging ROS, γ-tocopherol, in contrast to α-tocopherol, also reacts with reactive nitrogen species (RNS) such as peroxynitrite forming 5-nitro-γ-tocopherol (Patel et al., 2007). The γ-tocopherol scavenging of RNS may be beneficial for inflammation with increases in RNS such as neutrophilic inflammation induced by ozone or by endotoxins in mice (Fakhrzadeh et al., 2004). In the endotoxin-induced lung-inflammation model, administration of aerosol α-tocopherol (30 µg/rat) immediately before inhalation of a lipopolysaccharide (LPS) reduces lung neutrophilia, TNF-α, and cytokine-induced neutrophil chemoattractant-1 (Hybertson et al., 1995). However, in these studies, the source and purity of the α-tocopherol, as well as the lung tissue levels of tocopherols, were not determined. Lung neutrophilia is also reduced in an LPS inflammation model when liposomes containing α-tocopherol (50 mg α-tocopherol/kg mouse) were administered; however, there was no effect on blood neutrophil numbers, TNF-α, IL-1β, or MIP-1α (Rocksen et al., 2003). In asthmatic children exposed to ozone, vitamin E and C supplementation reduces IL-6 in nasal lavages, although the isoform of vitamin E was not indicated (Barthel et al., 2008). Nebulized γ-tocopherol reduces neutrophilia, IL-8, and IL-6 in burn and smoke inhalation injury models in sheep (Wardlaw, 2004). Consistent with this, supplementation with a mixture of tocopherols enriched for γ-tocopherol blocks acute endotoxin-stimulated or ozone-stimulated neutrophil inflammation in the rat and human lung (Hernandez et al., 2013; Wagner et al., 2009; Wiser et al., 2008). In another study, γ-tocopherol supplementation reduced antigen induction of rat lung inflammation in which there was several fold more neutrophils than eosinophils (Wagner et al., 2008). Therefore, γ-tocopherol may be of benefit for acute neutrophilic inflammation. In a study with ex vivo treatment of human macrophages, 300 µM γ-tocopherol decreased macrophage phagocytosis via modulation of surface receptor activity (Wardlaw, 2004). However, such highly elevated γ-tocopherol levels are not achievable in vivo. An important point to note is that although high levels of tocopherols have been used clinically, they can have adverse effects on the brain in animals and humans (Wardlaw, 2004). In contrast to reports of γ-tocopherol benefits in neutrophilic inflammation, it is reported that plasma γ-tocopherol associates with lower lung function in humans (Marchese et al., 2014) and with increased lung eosinophilia and airway hyper-responsiveness in mouse models of allergic asthma (Marchese et al., 2014). Therefore, chronic consumption of γ-tocopherol may be detrimental during lung development or chronic inflammatory diseases such as allergies and asthma. Further mechanistic clinical studies of tocopherol regulation of allergic lung inflammation are needed.

Tocopherol isoforms also have nonantioxidant functions that regulate cell signaling. Tocopherols have a relatively similar capacity to inhibit activation of protein kinase B (Akt) in cancer cells in vitro (Huang et al., 2013), and α-tocopherol inhibits activation of protein kinase Cα (PKCα) in cell systems or cell extracts (Mahoney and Azzi, 1988). Moreover, it is demonstrated that α-tocopherol and γ-tocopherol can directly regulate enzyme activity (McCary et al., 2012). For example, α-tocopherol and γ-tocopherol bind to PKCα at the C1a regulatory domain of PKCα (McCary et al., 2012). On binding, γ-tocopherol increases recombinant PKCα activity whereas α-tocopherol decreases recombinant PKCα activity (McCary et al., 2012), thereby demonstrating opposing regulatory functions for these tocopherol isoforms during cell signaling. Thus, α-tocopherol functions as an antagonist of PKCα activity and γ-tocopherol functions as an agonist of PKCα activity (McCary et al., 2012).

Asthma and Allergic Lung Inflammation

The World Health Organization has reported a worldwide increase in asthma and allergies ever since 1950 (Friebele, 1996; Vollmer et al., 1998). In 2012–13, the US Centers for Disease Control and Prevention reported asthma and allergy prevalence as 10–20% and affecting about 26 million people and costing $56 million/year and averaging nine deaths per day (CDC, 2012; Akinbami et al., 2012). Current therapies, including corticosteroids, have serious side effects, so it is critical to determine mechanisms for regulating inflammation in allergies and asthma in order to identify novel approaches for interventions. In humans, measurements of lung function include forced expiratory volume (FEV) in 1 s (FEV1: forced volume blown out in 1 s) and forced vital capacity (FVC), which is forced volume when all air is blown out. Asthma is characterized by inflammatory processes with T-helper (Th) cell responses of the Th2 phenotype being considered crucial for the initiation and perpetuation of the inflammatory responses (Palli et al., 2003). Important mediators of asthma and allergic inflammation are cytokines such as the interleukins IL-4, IL-5, and IL-13. Asthmatic and allergic inflammation is characterized by elevated immunoglobulin E, mast cell degranulation, and eosinophilic inflammation (Fiscus et al., 2001). Recruitment of eosinophils is a consistent feature of allergic inflammation and allergic asthma (Chin et al., 1997; Hakugawa et al., 1997; Sagara et al., 1997). A crucial component of recruitment of eosinophils during inflammation is leukocyte migration from the blood and across the endothelium and into the tissue (transendothelial migration) (Cook-Mills and Deem, 2005; Muller, 2011; Vestweber, 2012). Mechanisms for this eosinophil recruitment involve the coordinated actions of adhesion molecules, chemokines, and cytokines (Mould et al., 2000; Yang et al., 1998). Tocopherol isoform regulation of allergic inflammation has been studied in humans, animal models, and cell systems.

The increase in allergic inflammation and asthma may in part be influenced by the increase in γ-tocopherol consumption. In the past 50 years, there has been an increase in the γ-tocopherol isoform in the diet, in infant formulas containing soybean oil that is rich in γ-tocopherol, and in vitamin supplements (Cook-Mills and McCary, 2010; Uauy et al., 1994). Moreover, it has been suggested that early exposures to environmental factors increase the risk of allergic disease (Bousquet et al., 2011). Maternal exposure to environmental factors, including high fat diets, can alter neonatal hematopoietic or metabolic functions (Burke et al., 2009; Fedulov et al., 2008; Izzotti et al., 2003; Lim et al., 2010; Odaka et al., 2010; Rebholz et al., 2011; Vanhees et al., 2011; Woollett, 2005). In reports examining human maternal and paternal asthma associations with development of allergies in offspring, most associations are with maternal asthma (Lim and Kobzik, 2009a). In animal studies, the offspring of allergic mothers have increased responses to suboptimal doses of allergens (Lim and Kobzik, 2009a), and tocopherol isoforms regulate development of offspring responses (Abdala-Valencia et al., 2014, 2016). Therefore, studies of the regulation of adult allergies and asthma as well as the development of allergic disease and asthma early in life are critical to generating approaches to limit these diseases.

Clinical Studies of Asthma and Tocopherol Isoforms

Most clinical studies on vitamin E include mixed forms of natural and synthetic tocopherols from supplementation or diet. Some studies have reported what seem to be conflicting outcomes for vitamin E on allergies and other inflammatory diseases, but these differences are consistent with the differences in levels of tocopherol isoforms present in the study supplements, vehicles, and diets in the studies (Cook-Mills, 2012; Cook-Mills et al., 2011b; Cook-Mills and McCary, 2010) and consistent with mechanistic studies demonstrating that γ-tocopherol elevates allergic inflammation and that α-tocopherol reduces allergic inflammation (Abdala-Valencia et al., 2012a; Berdnikovs et al., 2009; Cook-Mills et al., 2011b; Marchese et al., 2014; McCary et al., 2011, 2012). In humans and mice, the tocopherol concentrations in plasma correlate with those in the lung tissue (Berdnikovs et al., 2009; McCary et al., 2011; Redlich et al., 1996). An interesting note is that countries with the highest prevalence rate of asthma tend to have higher plasma levels of γ-tocopherol (Cook-Mills et al., 2013; Cook-Mills and Avila, 2014). In the Unites States, the average human plasma γ-tocopherol levels are two to five times higher than those of many European and Asian countries, whereas the average levels of human plasma α-tocopherol is similar among all countries (Cook-Mills et al., 2013; Cook-Mills and Avila, 2014). The high human plasma γ-tocopherol levels in the United States are consistent with soybean oil consumption, which is high in γ-tocopherol (Abdala-Valencia et al., 2013; Cook-Mills et al., 2013; Cook-Mills and Avila, 2014; Jiang et al., 2001; Talegawkar et al., 2007). Most of the vitamin E consumed in the diet in the United States is γ-tocopherol in vegetable oils such as soybean oil, corn oil, and canola oil (Bieri and Evarts, 1973, 1975). Therefore, the high human plasma γ-tocopherol levels in the US population are consistent with high levels of γ-tocopherol in these oils (Table 17.1) (Choo et al., 2003; Davenpeck et al., 2000; Jiang et al., 2001; Miller et al., 2001). It has been demonstrated that soybean oil administration to humans and hamsters increases the plasma γ-tocopherol levels two- to fivefold (Meydani et al., 1987; Myou et al., 2002). In murine models of asthma with a two- to fivefold increase in plasma γ-tocopherol levels, there is an exacerbation of lung inflammation and suppression of the antiinflammatory functions of α-tocopherol (Berdnikovs et al., 2009).

Table 17.1

Tocopherol Isoforms in Dietary Oils

Oils Tocopherol (mg/100 g of oil)
α-T γ-T δ-T
Sunflower 56.27 ± 2.95a 1.22 ± 0.10 0.22 ± 0.02
Safflower 49.33 ± 6.88 3.85 ± 0.45 ND
Olive 6.13 ± 0.61 0.08 ± 0.004 ND
Grapeseed 7.58 ± 0.54 2.07 ± 0.12 0.11 ± 0.01
Soybean 7.82 ± 0.20 53.87 ± 0.09 15.99 ± 0.25
Corn 29.01 ± 3.21 46.69 ± 0.07 5.07 ± 1.38
Canola 16.45 ± 0.19 21.92 ± 0.05 0.13 ± 0.01
Peanut 14.41 ± 0.19 9.66 ± 0.27 0.80 ± 0.23
Sesame 77.68 ± 6.07 75.41 ± 4.82 56.27 ± 0.45

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ND, not detected.

aMean ± standard deviation.

Source: Adapted from Cook-Mills, J.M., Abdala-Valencia, H., Hartert, T., 2013. Two faces of vitamin E in the lung. Am. J. Respir. Crit. Care Med. 188, 279–284.

In contrast to its high levels in soybean oil, γ-tocopherol is low in other oils such as sunflower, safflower, and olive oil (Table 17.1), which are commonly used across Europe (Abdala-Valencia et al., 2013; Berdnikovs et al., 2009; Cook-Mills et al., 2013; Cook-Mills and Avila, 2014). These oils contain predominantly the α-tocopherol isoform (Abdala-Valencia et al., 2013; Cook-Mills et al., 2013; Cook-Mills and Avila, 2014). Also, in a study in which olive oil or soybean oil was administered to preterm human infants starting 24 h after birth, there was a significant 1.5-fold increase in plasma α-tocopherol after feeding with olive oil as compared to feeding with soybean oil, but unfortunately γ-tocopherol was not reported (Gobel et al., 2003). In countries with preferential consumption of safflower oil or olive oil, α-tocopherol supplementation of asthmatic patients in Italy and Finland was beneficial for outcomes of physician-diagnosed asthma and lung function as measured by FEV1 or wheeze (Dow et al., 1996; Smit et al., 1999; Tabak et al., 1999; Troisi et al., 1995; Weiss, 1997). Disappointingly, α-tocopherol was not beneficial for asthmatic patients in the United States or the Netherlands (Dow et al., 1996; Smit et al., 1999; Tabak et al., 1999; Troisi et al., 1995; Weiss, 1997), which have high plasma levels of γ-tocopherol and high intake of soybean oil. In contrast, administration of acetate-conjugated α-tocopherol oral supplementation at a very high dose (1500 IU, which is 1006 mg) to mild atopic asthmatics in the United States for 16 weeks resulted in increased plasma α-tocopherol, decreased plasma γ-tocopherol, and improved airway responsiveness to methacholine challenge (Hoskins et al., 2012). A meta-analysis study indicated that vitamin E has no association with asthma outcome measures of lung function and wheeze (Devaraj et al., 2007), but this did not take into account the opposing functions of α-tocopherol and γ-tocopherol. We interpret the results of this meta-analysis (Allen et al., 2009) as a combination of data across studies that included marked variation of vitamin E isoforms that have opposing functions and that were present in the diets, supplements, and supplement vehicles.

As countries assume Western lifestyles, diets may change and this would include an increased consumption of soybean oil (Devereux and Seaton, 2005). In two Scottish cohorts, it was reported that reduced maternal intake of vitamin E (likely referring to α-tocopherol) was associated with increased asthma and wheezing in children up to 5 years old (Devereux, 2007; Martindale et al., 2005). In Devereaux’s review of these data and changes in the environment in Scotland (Devereux, 2007) from 1967 to 2004, there was a significant increase in vegetable oil intake by Scottish residents, and we suggest that this would at least result in an increase in γ-tocopherol since vegetable oil (soybean oil) is rich in γ-tocopherol. In a study in England, dietary supplementation with α-tocopherol in soy oil to asthmatics had no impact on FEV1, asthma symptom scores, or bronchodilator use, but the γ-tocopherol in the soy oil may have opposed the benefit of the α-tocopherol (Pearson et al., 2004). Also, in a study in the United Kingdom, α-tocopherol administration in soybean oil to asthmatics did not have benefits (Hernandez et al., 2009) consistent with opposing functions of α-tocopherol and γ-tocopherol. There are also differences in asthma prevalence among racial and ethnic groups (Zahran and Bailey, 2013). However, studies examining tocopherol association with clinical outcomes generally adjust for several known confounding factors such as gender, age, body mass index, race, and smoking. Although there may be other differences regarding the environment and genetics of people in different countries, the outcomes for tocopherol isoforms and asthma in clinical studies are consistent with the studies demonstrating inhibitory functions of α-tocopherol and agonist functions of γ-tocopherol. Thus, the differences in outcomes of clinical reports mirror the opposing regulatory functions of α- and γ-tocopherol forms of vitamin E consumed in diets, supplements, and supplement vehicles (Berdnikovs et al., 2009). Our interpretation, supported by animal studies, is that the γ-tocopherol in soybean oil or other vehicles ablates the benefit of α-tocopherol supplementation in asthma. Therefore, differences in outcomes from clinical reports on the associations of vitamin E and asthma may, in part, reflect the opposing regulatory effects of α-tocopherol and γ-tocopherol in the supplements, the vehicles for the supplements, and diets in the individuals.

We reported that the findings of opposing regulatory functions of tocopherol isoforms in animal models can be translated to human lung function. In a prospective clinical study, 4526 adults were included in the United States in the Coronary Artery Risk Development in Young Adults (CARDIA) multicenter cohort with data for spirometry and serum tocopherol isoforms. In this cohort, there were equal numbers of blacks and whites and equal numbers of females and males by study design. Interestingly, increasing serum concentrations of γ-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of α-tocopherol were associated with higher FEV1 or FVC (Marchese et al., 2014). Since these two tocopherols have opposing functions, the analysis of opposing functions of tocopherol isoforms in clinical studies should include quartiles of plasma tocopherols with a determination of whether there is an association of a tocopherol isoform with the clinical outcome when the concentration of the opposing tocopherol is low and presenting the least competing opposing effects. Using this approach, in the analysis of the CARDIA cohort, plasma γ-tocopherol associates with lower lung function (FEV1) and plasma α-tocopherol associates with better lung function (FEV1) in nonasthmatics and asthmatics (Marchese et al., 2014) with adjustments for several known confounding factors such as gender, age, body mass index, race, and smoking. In the CARDIA cohort, a fivefold higher human plasma γ-tocopherol (>10 µM γ-tocopherol) was associated with reduced FEV1 and FVC in all participants (asthmatics and nonasthmatics) by ages 21–27. The γ-tocopherol-associated decreases in FEV1 and FVC before age 21 may occur during development and lung responses to environmental pollutants, allergens, or infections because tocopherols can directly regulate PKCα (Berdnikovs et al., 2009; Cook-Mills et al., 2011b; Cook-Mills and McCary, 2010; McCary et al., 2011). For the asthmatic group with plasma γ-tocopherol >10 µM, the participants had 350–570 mL lower FEV1 or FVC as compared to the low to moderate γ-tocopherol concentrations (<10 µM γ-tocopherol) at ages 21–27 (Marchese et al., 2014). This 10–17% decrease in FEV1 with >10 µM plasma γ-tocopherol in asthmatics is similar to the 5–10% reduction in FEV1 reported for other environmental factors. For example, individuals with occupational allergen exposure have a 5–8% decrease in FEV1 compared to nonasthmatics, and this decrease is associated with dyspnea, chest tightness, chronic bronchitis, and chronic cough (Jacobs et al., 1993). Responders to particulate matter have a 2–6% decrease in FEV1 (Delfino et al., 2004), responders to cold or exercise have a 5–11% decrease in FEV1 (Koskela et al., 1994), and responders to house dust mite or dog or cat dander have a 2–8% decrease in FEV1 (Blanc et al., 2005). Moreover, based on the 2% prevalence of serum γ-tocopherol >10 µM in adults in CARDIA and the adult US population in the 2010 Census, we expect that the lower FEV1 and FVC at >10 µM serum γ-tocopherol occur in up to 4.5 million adults in the US population. Thus, there are opposing outcomes for associating plasma α-tocopherol and γ-tocopherol with lung function in humans. This is consistent with mechanistic preclinical studies demonstrating opposing functions for α-tocopherol and γ-tocopherol (Abdala-Valencia et al., 2012a, 2014, 2016; Berdnikovs et al., 2009; Hess et al., 1997; McCary et al., 2011, 2012).

Adults and children with asthma have low plasma α-tocopherol levels (Al-Abdulla et al., 2010; Kalayci et al., 2000; Kelly et al., 1999; Schunemann et al., 2001). Plasma and tissue tocopherols correlate (Berdnikovs et al., 2009; McCary et al., 2011; Redlich et al., 1996). It is reported that patients with asthma have reduced α-tocopherol and ascorbic acid in airway fluid, but the average plasma concentration of α-tocopherol and ascorbic acid in these patients is normal (Kalayci et al., 2000; Kelly et al., 1999). Similarly, α-tocopherol and ascorbic acid levels are decreased in bronchoalveolar lavage of guinea pigs sensitized with ovalbumin (OVA) (Ratnasinghe et al., 2000). Tocopherol isoforms are also reduced in mice with allergic inflammation (Abdala-Valencia et al., 2014, 2016). Therefore, since α-tocopherol levels are low in asthmatics and α-tocopherol can reduce allergic inflammation, supplementation with physiological levels of natural α-tocopherol and maintenance of low dietary levels of γ-tocopherol in combination with other regimens may be an attractive strategy to either prevent or improve control of allergic disease or asthma. Based on average human plasma tocopherol isoforms in studied countries (Cook-Mills et al., 2013), prevalence of asthma in studied countries (Cook-Mills et al., 2013), and low α-tocopherol in asthma (Al-Abdulla et al., 2010; Kalayci et al., 2000; Kelly et al., 1999; Schunemann et al., 2001), a potential target for balancing tocopherol isoforms during allergic disease and asthma may be about 1–1.4 µM plasma γ-tocopherol and 22–30 µM plasma α-tocopherol (Fig. 17.2). Further intervention studies with analysis of the tocopherol isoforms in plasma are necessary to examine tocopherol isoform regulation of allergic lung inflammation and asthma in humans.

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Figure 17.2 Potential target for balance of human plasma α-tocopherol (α-T) and γ-tocopherol (γ-T) during allergic inflammation. Further studies are needed.

Comparing Tocopherol Doses in Humans and Preclinical Mouse Studies

For mouse models of disease, it is important to consider tocopherol doses for mice that might be relevant for humans. Ultimately, comparing doses for mice and humans is difficult because of differences in rates of metabolism. Relevant doses of tocopherol isoforms for studies in mice is a physiologic, nontoxic dose that achieves fold changes in mouse tissues similar to fold changes in human tissues. Basal α-T is necessary for mouse and human placental development (Jishage et al., 2005; Muller-Schmehl et al., 2004). For healthy adult humans, the recommended daily allowance of α-tocopherol is 15 mg/day. Doses of γ-tocopherol have not been addressed. Furthermore, whether doses higher than 15 mg α-tocopherol/day are necessary during disease has not been established. For mice, the standard basal mouse chow diet contains about 45 mg α-tocopherol/kg of diet and 45 mg γ-tocopherol/kg of diet (Abdala-Valencia et al., 2014, 2016). This results in about a 10-fold higher tissue α-tocopherol concentration than γ-tocopherol concentration (Abdala-Valencia et al., 2014, 2016) because of the preferential transfer of α-tocopherol by α-TTP in the liver.

Converting mouse doses to human doses is complex, so we briefly discuss translations of mouse α-tocopherol doses to human tocopherol doses. The basal mouse diet of 45 mg α-tocopherol/kg of diet is translated as follows:

[(45 mg α-tocopherol/kg of diet) × (1 kg/1000 g) × (6 g diet eaten/mouse/day)]/(28 g body weight for an adult mouse) × 65,000 g human adult)=627 mg α-tocopherol/day for human adult

However, mouse metabolism is about eightfold less efficient, and mice have a higher metabolic turnover rate per unit of body weight than humans (Kleiber, 1975; Terpstra, 2001). Thus, mice require about eightfold higher intake per gram of body weight. Furthermore, mice eat one-sixth their body weight in food/day (Bachmanov et al., 2002), which is considerably higher than the average amount of food/day for adult humans. Thus, to adjust for metabolic rate:

(627 mg/day for adult human)/(8 for metabolic rate difference)=78 mg α-tocopherol/day for human adults

For supplementation levels, a three- to fivefold increase in α-tocopherol for supplementation of mice during studies of inflammation (150 or 250 mg α-T/kg of diet for mice) is then 235–392 mg α-tocopherol/day for human adults (calculation: 78 mg/day × (3 or 5)). These supplemental doses are well below upper safety limits of 1,000 mg α-tocopherol/day in human pregnancy and near clinical levels in preeclampsia pregnancy trials of 268 mg (400 IU) α-tocopherol (Greenough et al., 2010; Gungorduk et al., 2014; Hauth et al., 2010; Kalpdev et al., 2011; McCance et al., 2010; Villar et al., 2009). Also, a supplemented mouse diet with 150 or 250 mg α-tocopherol/kg of diet is 30–60 times lower than the rodent maternal α-tocopherol diet dose that reduces rodent hippocampus function (Betti et al., 2011). The doses of 150 or 250 mg α-tocopherol/kg of diet for mice achieves a two- to threefold increase in tissue concentrations of α-tocopherol, which is similar to the fold tissue changes achievable in humans (Abdala-Valencia et al., 2012a; Berdnikovs et al., 2009; Cook-Mills et al., 2011a; Cook-Mills and McCary, 2010; McCary et al., 2011, 2012).

Alpha-Tocopherol and Gamma-Tocopherol Regulate Allergic Inflammation and Airway Hyper-Responsiveness in Preclinical Adult Animal Studies

Differences among reports for tocopherol regulation of eosinophilic lung inflammation may reflect differences in the intake of tocopherol isoforms and doses of tocopherols. Also, discrepancies among reports for tocopherol regulation of lung inflammation may be explained by an important parameter such as tocopherol isoforms used in the oil vehicle during supplementation. The levels of α-tocopherol and γ-tocopherol are different among dietary oils (Table 17.1) (Berdnikovs et al., 2009; Jiang et al., 2001; Wagner et al., 2004). High levels of γ-tocopherol are found in soybean, corn, canola, and sesame oils, so the administration of supplemental tocopherols in any of these vehicles would lead to misinterpretations. For example, Suchankova et al. (2006) reported that the administration of purified α-tocopherol in soy oil by gavage had no major effect on immune parameters or lung airway responsiveness in mice challenged with OVA. An interpretation is that high γ-tocopherol in the soy oil vehicle opposed the effect of the α-tocopherol, although tissue and plasma tocopherol levels were not reported for these studies. Okamoto et al. (2006) found that feeding mice α-tocopherol starting 2 weeks before antigen sensitization did not affect immunoglobulin E (IgE) levels but did reduce the number of eosinophils in the bronchoalveolar lavage, although the form and purity of α-tocopherol were not indicated. Mabalirajan et al. (2009) reported that oral administration of α-tocopherol in ethanol after antigen sensitization blocked OVA-induced lung inflammation and airway hyper-responsiveness. In this report, α-tocopherol treatment reduced airway hyper-responsiveness and mediators of inflammation, including IL-4, IL-5, IL-13, OVA-specific IgE, eotaxin, transforming growth factor beta (TGF-β), 12/15-LOX, lipid peroxidation, and lung nitric oxide metabolites (Mamdouh et al., 2009). Thus, supplementation with α-tocopherol alleviated allergic inflammation. For interpretation of studies with tocopherol isoforms, the vehicle, diet, and tissue concentrations of tocopherol isoforms need to be measured.

In mouse models of allergic lung responses to house dust mites, a mouse diet supplemented with 250 mg of α-tocopherol/kg during house dust mite challenges reduces eosinophilia in the lung (Cook-Mills et al., 2016). In contrast, a mouse diet supplemented with 250 mg γ-tocopherol/kg of diet elevated house dust mite–induced eosinophilia in the lung (Cook-Mills et al, 2016). Another mouse model of allergic lung inflammation is induced by sensitization with chicken egg OVA in adjuvant and followed by challenging the lung with inhaled OVA. In a study with the OVA model, the focus was on supplementation with tocopherols after OVA sensitization to determine whether tocopherol isoforms modulate the OVA antigen-challenge phase (Berdnikovs et al., 2009); this is relevant because patients are already sensitized. In this study, tocopherols were administered by daily injections after sensitization but before the allergen challenge (Berdnikovs et al., 2009). Subcutaneous administration of tocopherols achieves a plateau in levels of tissue tocopherols in a few days whereas dietary supplementation of tocopherols takes a couple of weeks to achieve a plateau in tissue tocopherol levels (Meydani et al., 1987; Mustacich et al., 2006). Administration of α-tocopherol or γ-tocopherol subcutaneously to allergic adult mice during challenge with OVA raises lung and plasma concentrations of the tocopherol isoform four- to fivefold without affecting body or lung weight (Berdnikovs et al., 2009). This fold change is achievable in humans. When tocopherols are administered subcutaneously or in the diet, the tocopherols enter the lymph and then the thoracic duct and the liver where the tocopherols are loaded on lipoproteins that enter circulation. Subcutaneous administration of γ-tocopherol elevates lung eosinophil recruitment by 175%, and α-tocopherol reduces lung eosinophil recruitment by 65% after challenge with OVA. Furthermore, in these mice, α-tocopherol blocks and γ-tocopherol increases airway hyper-responsiveness (Berdnikovs et al., 2009). The levels of tocopherols in these studies did not alter numbers of blood eosinophils, indicating that a sufficient number of eosinophils was available for recruitment (Berdnikovs et al., 2009). Also, the expression of adhesion molecules, cytokines, and chemokines required for the leukocyte recruitment was not compromised by tocopherol supplementation (Berdnikovs et al., 2009). This modulation of leukocyte infiltration in allergic inflammation without alteration of adhesion molecules, cytokines, or chemokines is similar to several other reports of in vivo inhibition of lung inflammation by inhibition of intracellular signals in endothelial cells (Abdala-Valencia et al., 2007, 2012b; Keshavan et al., 2005). The competing functions of tocopherol isoforms have important implications for the interpretation of clinical and animal studies of vitamin E regulation of inflammation.

Interestingly, γ-tocopherol negates the antiinflammatory benefit of α-tocopherol (Berdnikovs et al., 2009; McCary et al., 2011). Administration of both α-tocopherol and γ-tocopherol during challenge with OVA results in numbers of lung eosinophils and airway responses similar to those of the vehicle control treated allergic mice, suggesting that these two tocopherols have competing opposing functions. This strong opposing function of γ-tocopherol occurs even though γ-tocopherol is about 5–10 times lower in concentration in vivo than α-tocopherol. The proinflammatory allergic effects of γ-tocopherol in mice are partially reversed by switching supplements from γ-tocopherol to α-tocopherol for 4 weeks (McCary et al., 2011). It was also demonstrated that γ-tocopherol elevation of inflammation is fully reversible by highly elevated levels (10 times supplemental levels) of α-tocopherol (McCary et al., 2011). However, carefully considered should be the implications and adverse effects of high doses of tocopherols that may significantly increase the incidence of hemorrhagic stroke, elevated blood pressure, and increased all-cause mortality (Barthel et al., 2008; Wagner et al., 2004, 2008). Consequently, administration of very-high-dose α-tocopherol may be a potentially risky approach for reversing the proinflammatory effects of supplemental levels of γ-tocopherol. An alternative may be longer supplementation with modest levels of α-tocopherol.

In summary, the isoform α-tocopherol is antiinflammatory and blocks airway hyper-reactivity, and a fivefold increase in the isoform γ-tocopherol is proinflammatory and increases airway hyper-reactivity during eosinophilic allergic lung inflammation in adult mice (Abdala-Valencia et al., 2012a; Berdnikovs et al., 2009; Cook-Mills and McCary, 2010; McCary et al., 2011, 2012). These studies are consistent with the human studies, demonstrating that a fivefold increase in human plasma γ-tocopherol associated with a reduction in lung function in humans (Marchese et al., 2014). Furthermore, a fivefold difference in γ-tocopherol concentrations is consistent with fivefold higher γ-tocopherol in Americans versus Western Europeans and Asians and higher prevalence of asthma in Americans (Cook-Mills et al., 2013; Cook-Mills and Avila, 2014).

In allergic inflammation in the lung, eosinophil migration is dependent on the vascular cell adhesion molecule-1 (VCAM-1) whereas the other leukocytes can migrate on the intercellular adhesion molecule 1 (ICAM-1) (Chin et al., 1997; Sagara et al., 1997). These adhesion molecules signal through PKCα that can be directly regulated by tocopherol isoforms (McCary et al., 2012) as discussed previously. Thus, a mechanism for the opposing regulatory functions for α-tocopherol and γ-tocopherol on allergic inflammation in the mouse lung is, in part, a result of tocopherol regulation of signals for leukocyte transendothelial migration from the blood into the lung.

Tocopherol Regulation of Leukocyte Recruitment

During allergic inflammation, leukocytes are recruited from the blood into the tissues by migrating across the vascular endothelial cells. The migration of leukocytes across endothelial cells is inhibited by pretreatment of the endothelial cells with α-tocopherol and elevated by pretreatment of the endothelial cells with γ-tocopherol (Berdnikovs et al., 2009). Endothelial cells pretreated with α-tocopherol plus γ-tocopherol result in an intermediate phenotype that is not different from the vehicle-treated control endothelial cells, indicating that α-tocopherol and γ-tocopherol have opposing regulatory functions during leukocyte recruitment (Berdnikovs et al., 2009). The opposing functions of α-tocopherol and γ-tocopherol on endothelial cells during leukocyte transendothelial migration can occur through direct regulation of mediators of signal transduction. Briefly, the recruitment of eosinophils to sites of allergic inflammation requires eosinophil binding to adhesion molecules on endothelial cells such as VCAM-1 and ICAM-1 (Chin et al., 1997). These adhesion molecules signal through protein kinase Cα (PKCα) for the recruitment of leukocytes (Abdala-Valencia et al., 2012a; Berdnikovs et al., 2009; Jourd'heuil et al., 1997).

On loading the endothelial cells with physiological tocopherol concentrations that are at the same concentrations of tocopherols in lung tissues in mice, it was demonstrated that α-tocopherol inhibits VCAM-1 and ICAM-1 activation of PKCα in endothelial cells, and this inhibition is opposed by pretreatment of endothelial cells with γ-tocopherol (Abdala-Valencia et al., 2012a; Berdnikovs et al., 2009; Jourd'heuil et al., 1997). Alpha-tocopherol is an antagonist of PKCα and γ-tocopherol is an agonist of PKCα on binding to the C1A regulatory domain of PKCα (McCary et al., 2012). Alpha-tocopherol has been also reported to inhibit PKCα activation in other cell systems or cell extracts, but the mechanisms for inhibition in these systems were not demonstrated (de Luis et al., 2005). In summary, PKCα is differentially regulated by tocopherol isoforms in endothelial cells, which is critical for leukocyte recruitment in allergic lung inflammation and airway hyper-responsiveness.

Maternal Tocopherols and Offspring Development of Allergy

Clinical Studies of Maternal Tocopherols and Allergies and Asthma

The prevalence of allergies has increased in just a few decades, suggesting that environmental factors likely impact allergies and asthma because this is too short a time span for genetic alterations in whole populations. Environmental factors that regulate allergy and asthma in the mother could then affect the risk of development of allergy and asthma in offspring. Exposure to environmental factors such as chemical irritants or nutrients during pregnancy has been associated with allergic disease in offspring. An environmental change over the past 40 years that may contribute to elevating allergic responses has been an increase in the D-γ-tocopherol isoform of vitamin E in the diet and in infant formulas that contain soybean oil (Berdnikovs et al., 2009; Boyle et al., 1996; Cook-Mills and McCary, 2010; Nelson et al., 1996; Uauy et al., 1994).

Some studies suggest that development of allergen responsiveness may occur prenatally (Blumer et al., 2005; Devereux et al., 2002; Uthoff et al., 2003). In reports examining human maternal and paternal asthma associations with development of allergies in offspring, most associations are with maternal allergies or asthma (Celedon et al., 2002; Folsgaard et al., 2012; Kurukulaaratchy et al., 2003, 2005; Latzin et al., 2007; Lim et al., 2010; Litonjua et al., 1998; Martinez et al., 1995), suggesting that sensitization can occur prenatally or early postnatally. It is suggested that in utero and early exposures to environmental factors are critical for increased risk of allergic disease (Bousquet et al., 2011). There is an association of higher risk of eczema, wheezing, and lower respiratory tract infections in early life with increases in human maternal and cord blood C-reactive protein, which is an acute phase protein produced during inflammation (Sonnenschein-van der Voort et al., 2013).

Tocopherol isoforms may influence development of allergies early in life. It was demonstrated in a 20-year prospective study in the United States that by age 21 human plasma α-tocopherol associates with better lung spirometry and human plasma γ-tocopherol associates with worse lung spirometry (Marchese et al., 2014). This suggests that during human development prior to age 21, tocopherols may have regulatory functions on responsiveness to allergen. Thus, the balance of α-tocopherol and γ-tocopherol in women may regulate adult allergic responses (Marchese et al., 2014), and the balance of tocopherol isoforms in pregnant females may influence the development of risk of allergies in her children. It was demonstrated that maternal α-tocopherol dietary intake was inversely associated with cord blood mononuclear cells proliferative responses to allergen challenges (Devereux et al., 2002; Wassall et al., 2013). Also, maternal α-tocopherol supplementation of rats during pregnancy results in larger lungs with normal structure in offspring (Islam et al., 1999). Also, from ultrasound studies of the fetus, maternal α-tocopherol levels are reported to associate with fetal growth (Turner et al., 2010). In other clinical studies, α-tocopherol did not associate with asthma (Erkkola et al., 2001; Maslova et al., 2014; West et al., 2012), but these studies did not measure tocopherol isoforms or include analysis of potential opposing functions of γ-tocopherol.

Preclinical Studies of Maternal Contribution to Development of Offspring Allergy and Asthma

A mouse model for maternal transfer of risk of allergy to offspring reflects many of the parameters of development of allergic disease in humans, including increased risk for development of allergies in offspring of allergic mothers (Celedon et al., 2002; Fedulov and Kobzik, 2011; Fedulov et al., 2007; Folsgaard et al., 2012; Hamada et al., 2003; Kurukulaaratchy et al., 2003, 2005; Latzin et al., 2007; Leme et al., 2006; Lim and Kobzik, 2009a; Lim et al., 2010; Litonjua et al., 1998; Martinez et al., 1995). Moreover, as in humans, in this mouse model the allergic responses of the offspring are not specific to the allergen of the mother (Hamada et al., 2003). In the mouse model of maternal transfer of risk of allergy to offspring, allergy is induced in female mice by sensitizing with OVA in the adjuvant alum in the first 2 weeks and then challenging with OVA three times on weeks 4, 8, and 12 (Fedulov and Kobzik, 2011; Fedulov et al., 2007; Hamada et al., 2003). After the last OVA challenge in week 12, these female mice are mated. Therefore, the female mice have allergic lung inflammation during the first half of the pregnancy because it takes about 2 weeks for a resolution of allergic lung inflammation, which is the majority of the 3 weeks of mouse gestation. This is consistent with humans who have allergen-challenged pregnancies. Additional challenge of mice with OVA during pregnancy is not necessary for induction of risk of allergy in the offspring (Hamada et al., 2003). To determine allergen responsiveness in the offspring, all of the offspring from allergic mothers and nonallergic mothers are treated with a suboptimal OVA protocol. The suboptimal protocol includes neonates receiving only one instead of two OVA–alum treatments at postnatal days 3–5; then starting 7 days later, the neonates are challenged with aerosolized OVA for three consecutive days. The offspring of these allergic mothers develop allergic lung inflammation and airway responsiveness, whereas pups from nonallergic mothers do not develop inflammation in response to the allergen challenge. Moreover, this ability of the offspring of allergic mothers to respond to allergen is sustained for up to 8 weeks of age in the mouse (Fedulov et al., 2007). The magnitude of the offspring response to an initial allergen challenge declines in the offspring after 8 weeks (Fedulov et al., 2007). Allergic responses are inhibited in the mother by anti–IL-4 antibody administration to the mothers at preconception, and this maternal anti–IL-4 treatment blocks development of responsiveness of offspring to suboptimal allergen (Hamada et al., 2003). These data suggest that an IL-4–dependent allergic response in the mother is involved in the transmission of risk to the offspring. However, IL-4 and IgE do not pass to the fetus from the mother (Leme et al., 2006; Lim and Kobzik, 2009b; Uthoff et al., 2003). Th2 cytokines (IL-4, IL-5, and IL-13) are elevated in the placenta, but transplacental crossing of these cytokines has not been demonstrated (Bowen et al., 2002; Ostojic et al., 2003; Zourbas et al., 2001). It is reported that only 2% of maternal granulocyte macrophage–colony stimulating factor (GM-CSF) crosses the human placenta in ex vivo perfusate studies (Gregor et al., 1999). Whether maternal GM-CSF increases risk of offspring for allergic responses is not known. It was reported that antibody depletion of T cells in allergic mothers modulates the development of responsiveness of offspring to allergen (Hubeau et al., 2007). In other studies, adoptive transfer of allergen-specific T cells from OVA TCR transgenic mice DO11.10 mice to females prior to mating results in offspring with responsiveness to suboptimal challenge of antigen (Hubeau et al., 2006). These data suggest that maternal Th2 responses induce maternal signals that induce development of allergen responsiveness in offspring. Thus, female mice that are allergic before conception and develop a Th2 response during pregnancy produce offspring that have augmented responsiveness to suboptimal allergen challenge. Understanding mechanisms of maternal transfer of risk for allergy to offspring and mechanisms for regulation of this risk will have impact on limiting the development of allergic disease early in life.

The responses of the offspring from allergic mothers are not specific to the allergen to which the mother responds. Uthoff et al. (2003) reported that allergens can cross the placenta but that offspring are responsive to β-lactoglobulin whereas mothers were stimulated with OVA, suggesting that the process is antigen-independent. The antigen-independent maternal transfer of risk of allergy to offspring was also demonstrated (Hamada et al., 2003). In their report, offspring are responsive to casein, whereas the mothers were sensitized and challenged at preconception with OVA (Hamada et al., 2003). An antigen-independent effect of maternal allergy on allergen responsiveness in pups has also been demonstrated in canines (Barrett et al., 2003). Similarly, in humans, children respond to different allergens than the allergic mother. Thus, the offspring responses are not specific to the allergen that the mother responds to; instead, the offspring have an increased responsiveness to sensitization to allergens.

The sensitization to allergens and allergic responses are dependent on dendritic cells (DCs) which produce regulatory cytokines (van Rijt and Lambrecht, 2005; Williams et al., 2013). Interestingly, there are functional changes in the DCs from offspring of allergic mothers (Fedulov and Kobzik, 2011). Offspring from allergic mothers have increased allergic responsiveness to suboptimal allergen challenge (Abdala-Valencia et al., 2014; Fedulov and Kobzik, 2011; Hamada et al., 2003; Lim et al., 2007; Lim and Kobzik, 2009a), and this increased responsiveness of the offspring occurs through changes in pup DCs but not in pup macrophages (Fedulov and Kobzik, 2011). In these studies, the transfer of splenic DCs from nonchallenged neonates of allergic mothers into neonates from nonallergic mothers confers increased allergic susceptibility in recipient neonates (Fedulov and Kobzik, 2011). In contrast, the transfer of macrophages from nonchallenged neonates of allergic mothers into neonates from nonallergic mothers does not confer increased allergic susceptibility in recipient neonates (Fedulov and Kobzik, 2011). This is suggestive of a functional change in neonatal DCs in offspring from allergic mothers. Changes in DCs are consistent with the antigen-independent transfer of risk from allergic mothers to offspring in humans and in animal models.

Offspring of allergic mothers have an increase in a distinct subset of DCs. The fetal livers from allergic mothers and the OVA-challenged pup lungs from the offspring of allergic mothers have increased numbers of CD11b+ subsets of CD11c+ DCs (Abdala-Valencia et al., 2014), a DCs subset that is critical for generating allergic responses (Williams et al., 2013). In contrast, in these tissues, there are no changes in CD11b–regulatory DC subsets, including plasmacytoid DCs and CD103+ DCs (Abdala-Valencia et al., 2014). Furthermore, before antigen challenge of the pups, the DCs of pups from allergic mothers had little transcriptional changes but extensive DNA methylation changes (Mikhaylova et al., 2013). Then, after allergen challenge, there were many transcriptional changes in the DCs (Mikhaylova et al., 2013). These studies suggest that mediators, that do not confer allergen specificity, may be transferred from the mother to the offspring and these mediators regulate offspring DCs and heighten the responsiveness of offspring to challenge with suboptimal doses of allergens. This is consistent with the clinical reports demonstrating that the risk for allergy in children has been associated with mothers with existing allergic disease before conception (Celedon et al., 2002; Folsgaard et al., 2012; Kurukulaaratchy et al., 2003, 2005; Latzin et al., 2007; Lim et al., 2010; Litonjua et al., 1998; Martinez et al., 1995).

It has been reported that there is a role of breast milk of allergic mother mice on development of offspring allergic responses. However, the milk of allergic mothers is not necessary for the offspring allergic responses because the in utero maternal effects are sufficient for allergic responses by the offspring of allergic mothers. This was demonstrated by cross-fostering the offspring. Briefly, pups from allergic mothers that are nursed by nonallergic mothers still have an allergic response to suboptimal challenge with OVA (Leme et al., 2006). Therefore, maternal effects in utero mediate development of allergen responsiveness in the offspring of allergic mothers (Leme et al., 2006). Breast milk is sufficient, but not necessary, for maternal transmission of asthma risk in the offspring because when pups from nonallergic mothers are nursed by allergic mothers, the pups exhibit a response to suboptimal allergen challenge (Leme et al., 2006). In this study, the breast milk from allergic and nonallergic mothers contained no detectable interferon-γ (IFN-γ), IL-2, IL-4, IL-5, IL-13, or TNF-α, suggesting that other mediators increase the risk of offspring allergy through breast milk (Leme et al., 2006). In clinical studies, it is reported that the mediators, omega-3 and omega-6 polyunsaturated fatty acids, in human milk associate with asthma and atopy, but the mechanism is not known (Reichardt et al., 2004; Stoney et al., 2004). It is also reported that omega-3 fatty acids during pregnancy associates with lower infantile wheeze (Miyake et al., 2011).

In contrast to studies in which the mother mice were allergic before conception, the function of breast milk has been studied in female mothers that were not allergic at preconception. In these models, the nonallergic mother mice were exposed during pregnancy or lactation to an allergen or an antigen tolerance protocol. In mouse models in which the mother was not allergic at preconception but then exposed during pregnancy or lactation to an allergen or an antigen tolerance protocol, there was protection of offspring responses to allergen sensitization and challenge. Briefly, it is reported that the exposure of normal female mice during lactation to OVA results in the transfer of antigen and TGF-β in milk, and this inhibited allergic inflammation in offspring treated later as adults (6–8 weeks old) with two sensitizations with OVA–alum and five OVA challenges (Verhasselt et al., 2008). These adult offspring also had elevated regulatory CD4+ T cells, and the increase in T regulatory cells was dependent on milk TGF-β but not milk immunoglobulins (Verhasselt et al., 2008). In another approach, it was demonstrated that sensitization of females before mating and then extensive antigen challenges (10 OVA challenges) during lactation resulted in the transfer of IgG immune complexes in the milk and the induction of regulatory T cells and tolerance in the offspring when offspring were challenged with OVA at 6–8 weeks old; in this model, immune complexes but not TGF-β in the milk was required for tolerance (Mosconi et al., 2010). In summary, depending on timing, doses, and the number of antigen challenges, factors in breast milk can contribute mediators that either increase or decrease offspring responses to allergen.

One endogenous transplacental maternal mediator in mice may contribute to the increased responsiveness in the offspring to a suboptimal OVA challenge (Lim et al., 2014). This mediator is increased but is still low-level maternal corticosterone (Lim et al., 2014). In adult mice and rats, OVA sensitization and challenge increases stress (Costa-Pinto et al., 2005, 2006; Portela Cde et al., 2001, 2002, 2007; Tonelli et al., 2009) and increases endogenous serum corticosterone (Chida et al., 2007; Lu et al., 2010). Moreover, it is reported that symptoms of stress or anxiety are commonly associated with allergy or asthma in adult mice and in humans (Cheung et al., 2009; Cordina et al., 2009; Di Marco et al., 2010; Sansone and Sansone, 2008; Strine et al., 2008). When maternal corticosterone is elevated during pregnancy, the maternal cortisol can cross the placenta and affect fetal cortisol levels (Huang et al., 2012; von Hertzen, 2002). Other researchers have reported that maternal corticosterone crosses the placenta to the fetus and is a strong inducer of Th2 responses (Norbiato et al., 1997; Ramirez et al., 1996). Cortisol is also present in human breast milk (Groer et al., 1994) and has the potential to affect allergic responses in neonates. Consistent with the mechanistic studies in mouse models, in pregnant asthmatic women without treatment for asthma, a deficiency in the placenta of a cortisol-metabolizing enzyme 11-beta-hydroxysteroid dehydrogenase 2 leads to increased fetal cortisol and low birth weight, which is predictive of lower lung function later in life (Murphy et al., 2002, 2003).

It has been reported that stress in adult 4-week-old mice exacerbates OVA-induced allergic responses and that this stress-induced effect is blocked by pretreatment with a glucocorticoid receptor antagonist (Chida et al., 2007). It has also been demonstrated that subjecting pregnant female mice to stress increases endogenous corticosterone, offspring allergic responses to suboptimal allergen, and offspring airway responsiveness after suboptimal allergen challenge (Lim et al., 2014; von Hertzen, 2002). Furthermore, glucocorticoid during pregnancy is sufficient for allergic responses in offspring because administration of a low dose of glucocorticoid to nonallergic mothers on day 15 of gestation increases offspring allergic responsiveness to suboptimal allergen challenges (Lim et al., 2014). In addition, when these mothers are subjected to stress and treated during pregnancy with an inhibitor of endogenous corticosterone synthesis, there is a reduction in the allergic response by the offspring (Lim et al., 2014). Therefore, elevated corticosterone in allergic pregnant mice might be a mediator that is transferred from the mother to the fetus or in the breast milk to the neonate, resulting in enhanced responses of offspring to suboptimal allergen challenge. This mechanism is consistent with the antigen-independent transfer of risk from mother to offspring for allergic responsiveness (Barrett et al., 2003; Hamada et al., 2003).

A maternal effect on offspring allergic responses has also been demonstrated for maternal exposure to environmental irritants. Maternal inhalation of titanium oxide or diesel exhaust particles during pregnancy increased responses of offspring to allergen challenges (Fedulov et al., 2008). Also, skin sensitization to toluene diisocyanate (TDI) induces a Th2 response in the mother; when the mother was mated after a second dose of TDI, the offspring had increased allergic responses to suboptimal OVA (Lim et al., 2007). In contrast, a Th1 response in the mother may protect the offspring from developing allergic responses. When females are sensitized to dinitrochlorobenzene which induces a Th1 response, and then mated, the offspring do not develop an allergic response to suboptimal OVA (Lim et al., 2007). Also, offspring are protected from development of asthma by prenatal challenge of the mother with LPS, which induces a Th1 inflammation, an increase in IFN-γ, and a decrease in IL-5 and IL-13 (Gerhold et al., 2002, 2003, 2006; Tulic et al., 2001). Injection of nonallergic mothers with IFN-γ on gestational day 6.5 protects against the development of allergic responses in offspring (Lima et al., 2005). Fedolov et al. (2005) demonstrated that treatment of the offspring from allergic mothers on postnatal day 4 with cytosine guanine oligonucleotides, a toll-like receptor-9 agonist and Th1-type stimulant, (de Brito et al., 2010) protected the offspring from development of allergic responses to suboptimal OVA challenges. Therefore, exposure of mothers, allergic mothers, or offspring from allergic mothers to a Th1 stimuli inhibited offspring responses to allergen challenge.

Maternal α-Tocopherol Supplementation Reduces Allergic Responses in Offspring in Preclinical Models

In mice, α-tocopherol supplementation of allergic female mice during pregnancy or lactation decreases neonate development of allergic lung inflammation in response to suboptimal allergen challenges (Abdala-Valencia et al., 2014). In these studies, allergic responses to OVA were induced in adult female mice, who were then mated while receiving α-tocopherol–supplemented diets (250 mg α-tocopherol/kg diet) or a basal α-tocopherol diet (45 mg α-tocopherol/kg diet) (Abdala-Valencia et al., 2014). A basal α-tocopherol diet is used as the control because adequate α-tocopherol levels are required for placental development (Jishage et al., 2005; Muller-Schmehl et al., 2004). Then, the 3-day-old neonates received a suboptimal allergen sensitization with OVA–alum and OVA-challenge on days 10–12 (Abdala-Valencia et al., 2014). The α-tocopherol–supplemented diet significantly increases liver α-tocopherol in the saline-treated mothers threefold compared to basal diet controls. The OVA-induced allergic response reduces the α-tocopherol tissue concentrations in the α-tocopherol–supplemented mothers, which is consistent with reduced α-tocopherol levels in asthmatics (Kalayci et al., 2000; Kelly et al., 1999; Schunemann et al., 2001; Shvedova et al., 1995), suggesting that α-tocopherol supplementation may be especially necessary for asthmatic mothers. Maternal α-tocopherol supplementation increases pup liver α-tocopherol 2.5-fold (Abdala-Valencia et al., 2014). The α-tocopherol supplementation of allergic mothers during pregnancy and lactation results in a dose-dependent inhibition of lung eosinophils (Abdala-Valencia et al., 2014) in the OVA-stimulated pups from allergic mothers as compared to OVA-challenged pups from nonallergic mothers (Abdala-Valencia et al., 2014). There is no effect of tocopherol or OVA treatments on pup weight, pup numbers, or pup gender distribution (Abdala-Valencia et al., 2014). OVA-treated pups from allergic mothers increase serum IgE, but α-tocopherol supplementation does not alter the IgE (Abdala-Valencia et al., 2014). Maternal α-tocopherol supplementation of allergic female mothers inhibits OVA-induced pup lung mRNA expression of cytokines that regulate allergic inflammation (IL-33 and IL-4) and chemokines for eosinophil recruitment (CCL11 and CCL24) (Abdala-Valencia et al., 2014). Therefore, α-tocopherol supplementation of allergic mothers inhibits allergic inflammation and cytokine or chemokine mediators of allergic inflammation in OVA-challenged pups from these allergic mothers.

In studies to determine the regulatory effect of α-tocopherol in utero and in the milk, pups were cross-fostered at birth. Cross-fostering pups from allergic mothers with 250 mg α-tocopherol/kg diet to allergic mothers with a basal diet (45 mg α-tocopherol/kg diet) indicated that α-tocopherol supplementation of the allergic mother during pregnancy was sufficient to inhibit the OVA-induced increase in neonate lung eosinophils (Abdala-Valencia et al., 2014). In addition, α-tocopherol supplementation during lactation reduces the allergic responses in the neonates (Abdala-Valencia et al., 2014), suggesting a contribution of α-tocopherol after birth (Abdala-Valencia et al., 2014). In summary, α-tocopherol supplementation of allergic mothers during pregnancy is sufficient to reduce development of allergic responses in the offspring.

Supplementation with α-tocopherol starting at conception of a second pregnancy of allergic female mice also inhibits development of allergic lung inflammation in their offspring. The offspring from allergic mothers that were supplemented with α-tocopherol at the time of the second mating had >90% inhibition of lung lavage eosinophils in the OVA-challenged pups (Abdala-Valencia et al., 2014). Moreover, in OVA-challenged pups from allergic mothers, α-tocopherol reduces pup lung mRNA expression of several mediators of allergic inflammation: the cytokines IL-4, IL-33, and thymic stromal lymphopoietin and the chemokines CCL11 and CCL24 (Abdala-Valencia et al., 2014). This is consistent with α-tocopherol regulation of the development of allergic inflammation. There are no effects of maternal α-tocopherol supplementation on pup low levels of the Th1 cytokine IFN-γ or the regulatory cytokine IL-10 (Abdala-Valencia et al., 2014), which indicates that α-tocopherol does not switch the response to OVA to a Th1 response.

Maternal Gamma-Tocopherol Supplementation Elevates Allergic Responses in Offspring in Preclinical Models

In studies with maternal diets supplemented with a 250-mg γ-tocopherol/kg diet, maternal γ-tocopherol raises the maternal liver γ-tocopherol level twofold and the pup liver γ-tocopherol fivefold, which is consistent with the fold tocopherol changes in human and mouse tissues after supplementation (Abdala-Valencia et al., 2012a; Berdnikovs et al., 2009; Cook-Mills et al., 2011a; Cook-Mills and McCary, 2010; McCary et al., 2011, 2012). Supplementation of allergic female mice with γ-tocopherol elevates neonatal development of lung eosinophils in offspring challenged with suboptimal doses of allergen (Abdala-Valencia et al., 2016). The γ-tocopherol does not induce allergic inflammation because it does not increase allergic inflammation in the pups from nonallergic mothers. In pups from allergic mothers, maternal d-γ-tocopherol supplementation increases inflammatory mediators, including the Th2 mediator amphiregulin, IL-5, CCL11, CCL24, activin A, and GM-CSF. Of potential relevance and concern, maternal γ-tocopherol supplementation also decreases the numbers of mated females that had pups, but it did not affect the numbers of pups per litter or pup body weight. Basal levels of α-tocopherol are required for placentation (Jishage et al., 2005; Muller-Schmehl et al., 2004), but it is not known whether γ-tocopherol influences placentation. Whether γ-tocopherol regulates placenta development or other functions during development is not known. Nevertheless, the reduced numbers of mothers with pups and increased pup allergic responses with γ-tocopherol supplementation has potential important implications for allergic mothers consuming γ-tocopherol in their diet or prenatal vitamins and for infants consuming infant formulas supplemented with γ-tocopherol.

Maternal Gamma-Tocopherol Supplementation Elevates and Maternal α-Tocopherol Supplementation Reduces Dendritic Cell Development

It has been reported that the transfer of DCs but not macrophages from pups born to allergic mothers to the pups of nonallergic mothers are sufficient for the development of the allergic responses in recipient pups in response to suboptimal OVA challenge (Fedulov and Kobzik, 2011). Furthermore, lungs of allergen-challenged offspring from allergic mothers have elevated numbers of a distinct subsets of lung DCs (CD11b+CD11c+ resident and alveolar DCs) but there are no changes in numbers of CD11b–CD11c+ DCs (plasmacytoid DCs and CD103+ DCs) (Abdala-Valencia et al., 2014). During fetal development, hematopoiesis occurs in the fetal liver. In gestational day 18 fetal livers of allergic mothers, there is an increase in DCs of the phenotype of CD11b+CD11c+ resident DCs (Abdala-Valencia et al., 2014). Therefore, there is an effect of maternal allergy on the development of distinct subsets of DCs in the fetus.

The increase in the numbers of DC subsets in offspring of allergic mothers is regulated by α-tocopherol. Maternal supplementation with α-tocopherol significantly reduces the OVA-stimulated pup lung numbers of CD11b+ subsets of CD11c+ DCs, including resident DCs, myeloid DCs, and CD11b+ alveolar DCs, without altering CD11b– subsets of CD11c+ DCs, including plasmacytoid DCs, CD103+ DCs, CD11b– alveolar DCs, and alveolar macrophages (Abdala-Valencia et al., 2014). It is interesting that α-tocopherol supplementation does not completely deplete CD11b+ DCs; instead, α-tocopherol supplementation of allergic mothers reduces the numbers of pup CD11b+ DCs to the numbers of these DCs in pups from nonallergic mothers (Abdala-Valencia et al., 2014). For all DCs subsets, the cell surface mediators MHCII, CD80, and CD86 are not different among the groups in the pup lungs (Abdala-Valencia et al., 2014). Furthermore, in the fetus on gestational day 18, α-tocopherol supplementation of allergic mothers reduces the number of fetal liver CD11b+ subsets of CD11c+ DCs, including those of the phenotype of myeloid DCs and phenotype of resident DCs without altering expression of MHCII, CD80 or CD86 (Abdala-Valencia et al., 2014). The fetal liver CD11b- subsets of CD11c+ DCs are not altered by maternal supplementation of α-tocopherol (Abdala-Valencia et al., 2014). Thus, the specificity of tocopherol regulation of the CD11b+ DC subsets in the fetus suggests that tocopherols may regulate signals for DC differentiation of these DC subsets or regulate signals for expression of CD11b.

In contrast to maternal α-tocopherol supplementation, maternal supplementation with γ-tocopherol increases development of CD11c+CD11b+DCs but not the numbers of pup lung CD11b–DC subsets in allergen-challenged lungs of neonates (Abdala-Valencia et al., 2016). In addition, there is an increase in neonatal cytokines, chemokines, and lung CD11b+IRF4+DC subsets that are critical to development of allergic responses. The γ-tocopherol supplementation of allergic mothers also increases the generation of IRF4+CD11c+CD11b+DCs in the fetal liver on GD18 (Abdala-Valencia et al., 2016). In the gestational day 18 fetal livers of γ-tocopherol–supplemented mothers, there are fewer regulatory CD11b–CD11c+pDCs (Abdala-Valencia et al., 2016), suggesting that γ-tocopherol supplementation may see a reduced control of magnitude of responses to allergen challenge early in life. However, in the postnatal day 13 OVA-challenged pup lung, the number of pDCs was not altered with γ-tocopherol supplementation (Abdala-Valencia et al., 2016).

Maternal supplementation of allergic mothers with γ-tocopherol also partially increases mediators of allergic inflammation and DC subsets in the offspring of nonallergic mothers. Maternal D-γ-tocopherol supplementation partially increases the numbers of resident DCs in the fetus and OVA-challenged pup lung from nonallergic mothers but not to the extent as in the OVA-challenged pups from D-γ-tocopherol–supplemented allergic mothers (Abdala-Valencia et al., 2016). This is consistent with the increased GM-CSF with γ-tocopherol supplementation in pup lungs from allergic mothers (Abdala-Valencia et al., 2016). γ-tocopherol also increased activin A in pups from nonallergic and allergic mothers (Abdala-Valencia et al., 2016). Activin A is a member of the TGF-β superfamily of cytokines and regulates allergic inflammation (Hardy et al., 2015). Activin A is produced by several cell types including epithelium, endothelium, mast cells, fibroblasts and DCs and it can induce differentiation of monocytes to mDCs and recruitment of DCs (Hedger et al., 2011). Therefore, with maternal γ-tocopherol activin A may function in concert with other mediators to increase the numbers of DCs and allergic inflammation. In fact, γ-tocopherol increases CCL11 in pups from allergic and nonallergic mothers, and it increases CCL24 and IL-5 in the pups from nonallergic mothers (Abdala-Valencia et al., 2016). An OVA challenge in pups from allergic mothers with D-γ-tocopherol does not result in further increases in CCL24 or IL-5 (Abdala-Valencia et al., 2016), which may indicate that a maximum response was achieved with an OVA challenge. Nevertheless, the pups from the allergic mothers with D-γ-tocopherol have elevated CCL11 and amphiregulin, which suggests that, in combination, these signals as well as the presence of GM-CSF, CCL24, IL-5, and activin A may function to amplify recruitment of eosinophils in pups from allergic mothers with D-γ-tocopherol–supplemented diets.

There may be at least a direct effect of tocopherols on bone marrow DC differentiation. When bone marrow from 10-day-old mouse neonates from nonallergic mothers with basal diets are incubated with GM-CSF for 8 days in vitro in the presence of α-tocopherol, α-tocopherol supplementation of the culture reduces the number of CD45+ CD11b+ CD11c+DCs and the number of cells with resident DC phenotype (CD45+CD11b+CD11c+Ly6c-MHCII DCs) without affecting the percent of viable cells in the culture (Abdala-Valencia et al., 2014). Gamma-tocopherol has at least a direct effect on hematopoietic development of DCs because D-γ-tocopherol increases the generation of IRF4+CD11c+CD11b+ bone marrow–derived DCs in vitro (Abdala-Valencia et al., 2016). In addition, D-γ-tocopherol decreased the numbers of inhibitory PDCA+ plasmacytoid CD11c+CD11b–DCs in the fetal liver (Abdala-Valencia et al., 2016). There was no effect of D-γ-tocopherol on the level of expression of MHCII, CD80, or IRF4 by the fetal liver and pup lung DCs (Abdala-Valencia et al., 2016).

Thus, γ-tocopherol and α-tocopherol regulate generation of DCs and signals for allergic inflammation during development. Maternal supplementation with γ-tocopherol in mouse models increases allergic responses in offspring from allergic mothers and increases development of CD11c+CD11b+DC types in utero, in antigen-challenged neonate lungs, and in bone marrow cultures. Moreover, there is specificity of regulation of DCs by γ-tocopherol because γ-tocopherol supplementation increases the number of CD11c+CD11b+ but not CD11c+CD11b– DC types in pup lungs. There is also specificity of regulation of DCs in utero because maternal γ-tocopherol increases fetal liver CD11c+CD11b+ DCs and decreases the numbers of plasmacytoid regulatory DCs in the fetal liver. Supplementation with γ-tocopherol elevated several mediators of inflammation without altering OVA-specific IgE. Studies of γ-tocopherol regulation of inflammation provide a basis for designing drugs, supplements, and diets that more effectively modulate these pathways in allergic disease. Further studies are needed for the design of future clinical studies with vitamin E isoforms and on our understanding of vitamin E isoform regulation of DC function during allergic inflammation. The function of tocopherol isoforms on allergic inflammation and asthma may have implications for dietary impact on the risk of allergic disease in future generations. More studies are needed in humans to examine short-term versus long-term outcomes of a range of plasma concentrations of tocopherol isoforms.

Alpha-Tocopherol and Gamma-Tocopherol: Opposing Functions in Other Chronic Inflammatory Diseases

In addition to opposing functions of tocopherol isoforms in allergic disease, α-tocopherol and γ-tocopherol may have opposing outcomes for other diseases, including arthritis and cardiovascular. However, as with asthma, there are conflicting outcomes for vitamin E in these diseases. Briefly, human plasma γ-tocopherol positively associates with osteoarthritis, whereas plasma α-tocopherol negatively associates with osteoarthritis (Jordan et al., 2004). In coronary heart disease and stroke, studies of tocopherols and heart disease are complex because different dietary oils contain different lipids that affect heart disease. Nevertheless, for plasma γ-tocopherol, it is either not associated with heart disease or is associated with an increase in risk for myocardial infarction (Dietrich et al., 2006). In contrast, for α-tocopherol, it is either not associated with heart disease or is associated with reduced death from heart disease (Dutta and Dutta, 2003; Meydani, 2004; Munteanu and Zingg, 2007; Siekmeier et al., 2007). Therefore, for those reports with effects on heart disease, γ-tocopherol associates with an increase and α-tocopherol associates with a decrease in heart disease.

Conclusions

Epidemiological studies and randomized prevention trials have demonstrated the potential of a number of protective dietary factors for asthma, including α-tocopherol. However, these reports have seemingly varied outcomes regarding the benefits of supplementation with the α-tocopherol and γ-tocopherol isoforms of vitamin E. These discrepancies in clinical results are consistent with mechanistic studies of differential regulatory functions of these tocopherol isoforms in animal asthma models and in cell cultures with physiological doses of the tocopherol isoforms. Tocopherols also function beyond their antioxidant capacity and regulate signaling pathways essential in the inflammatory process. Specifically, supplementation with physiological levels of purified α-tocopherol and γ-tocopherol has opposing regulatory functions during inflammation such that α-tocopherol is antiinflammatory and γ-tocopherol is proinflammatory. Understanding the differential regulations of inflammation by isoforms of vitamin E provides a basis for designing drugs and diets that more effectively modulate inflammatory pathways and improve lung function in disease.

The marked differences in rates of asthma across the world, changes in disease prevalence over short periods, and changes with migrating populations means that environment influences the development and responses to triggers that worsen asthma and allergic inflammation. This means that changes in diet or lifestyle or both could modify disease. Going forward, studies in preclinical models and clinical studies need to be designed to include measurements of the tocopherol isoforms in the supplements, vehicles for the supplements, and the plasma or tissues. Moreover, in preclinical animal and clinical studies, tocopherol isoforms need to be measured prior to intervention and after interventions with tocopherol isoform-specific supplementation. These tocopherol measurements are necessary to clearly interpret study outcomes. Understanding the epidemiology, biology, and regulation of asthma inception by environmental factors will lead to approaches that could reduce the development of allergy and asthma. Further studies are necessary to define and provide a basis for recommendations for doses for tocopherol isoforms in normal and, more important, inflammatory disease states in adult human females and males as well as ethnic groups that differ in the prevalence of asthma (Kim et al., 2016; Sheikh et al., 2016). The therapeutic potential of dietary manipulation and supplementation in allergic pregnant mothers and children with asthma requires further work. The investigation of early life diet in relation to childhood asthma raises the possibility of early life dietary interventions.

Sources of Support: This study was supported by National Institutes of Health Grants R01 AT004837 and R01 HLB111624, and the Ernest S. Bazley Grant.

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