Joan Cook-Mills, PhD
Professor of Medicine
Background: Allergic disease and asthma result from complex interactions of environmental and genetic factors. The World Health Organization reported increased prevalence of asthma from 1950 to the present. 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 development of asthma. One of the environmental changes over the past 40 years has been an increase in the vitamin E isoform d-γ-tocopherol (γT) in the diet and in infant formulas that contain soybean oil which is rich in γT.
Results: We demonstrated that the vitamin E isoform d-α-tocopherol (αT) blocks allergic responses in adult mice. In contrast, a 5-fold increase in γ-T in tissues increases eosinophilic allergic lung inflammation (175%) and airway hyperresponsiveness in adult mice. In mechanistic studies of signals for recruitment of eosinophils to the site of allergic inflammation, we demonstrated that αT and γT bind the C1a regulatory domain of protein kinase Cα and compete with diacylglycerol and retinol for binding to the C1a domain. Moreover, αT and γT functioned as an antagonist and agonist of PKCα, respectively. To translate our findings for αT and γT to humans, we demonstrated that adults with high γT and low αT in plasma had increased odds of lower lung function by 4 fold in 8 years. In another clinical study, we demonstrated that a 5-fold higher plasma γT level associates with lower lung spirometry (10 to 17% decrease in FEV1) in adults by age 21, suggesting that early in life, tocopherol isoforms may regulate development and lung responses to environmental exposures such as allergens. Allergies often develop early in life and, importantly, offspring of allergic mothers have increased responsiveness to allergen challenge. In a mouse model, we demonstrated that in the fetal liver of allergic mothers, there is an increase in distinct subsets of CD11b+CD11c+ inflammatory dendritic cells and cytokines that regulate development of allergic responses. This increase in dendritic cells and cytokines was blocked by supplementation of the mother with αT but, elevated by supplementation of the mother with γT.
Conclusions: αT and γT have opposing regulatory functions in allergic responses and in development of allergic disease. The opposing regulatory functions of αT and γT impact interpretations of previous studies with disparities of vitamin E effects on inflammation in basic and clinical research. Moreover, our data have important implications for tocopherol regulation of the development of allergic disease in offspring and future generations.