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 environmental change over the past 40 years has been an increase in d-?-tocopherol (?-T) in the diet. In our mechanistic studies in adult mice, a 5-fold increase in ?-T elevates eosinophilic allergic lung inflammation (175%) and airway responses whereas a 5-fold increase in another tocopherol isoform, ?-T, blocks eosinophilic allergic responses (65% decrease). In mechanistic studies of signals for eosinophil recruitment in allergic asthma, we demonstrated that ?-T is an agonist and ?-T is an antagonist of protein kinase C? (PKC?). Moreover in our studies with adult humans, a 5-fold higher plasma ?-T level associates with better spirometry and a 5-fold increase in ?-T associates with lower spirometry (10 to 17% decrease in FEV1); this occurred by age 21, suggesting that early in life, tocopherol isoforms may regulate development and lung responses to environmental exposures. We propose a novel concept that early in life, ?-T and ?-T regulate the development of dendritic cells (DCs) and allergic disease. Consistent with our novel concept, we demonstrated that supplementation of allergic pregnant mice with ?-T increased and ?-T decreased pup allergic responses and subsets of lung CD11b+CD11c+ subsets of DCs that are critical to initiation of allergic inflammation. In addition, the inhibitory effect of ?-T early in life was sustained in the pups. In vitro, ?-T increased and ?-T decreased numbers of bone-marrow-derived DCs, suggesting at least a regulatory function of tocopherols on differentiation of DCs. Mechanisms for ?-T and ?-T regulation of the development of DCs and allergic responses are not known. Our long term goal is to identify mechanisms for ?-T and ?-T regulation of the development of DCs and allergic responses. As a step towards our long-term goal, our central HYPOTHESIS is that early in life, ?-T reduces and ?-T elevates mediators that regulate 1) allergic responses and 2) CD11b+CD11c+ DC development and function during the initiation of allergic lung responses. We will test our central hypothesis with the following aims:
Aim 1. Test the hypothesis that maternal ?-T reduces and ?-T elevates offspring cytokines and growth factors that regulate development of DC and T cell responses to allergen early in life.
Aim 2. Test the hypothesis that ?-T inhibits and ?-T elevates DC PKC activity during CD11b+CD11c+ DC differentiation and activation and T cell PKC activity during DC activation of T cells. Successful completion of these studies will have a significant impact on 1) our understanding of mechanisms of ?-T and ?-T regulation of DCs during development of allergies and 2) the design of clinical studies with ?-T and ?-T. Furthermore, these studies will provide a basis for design of interventions that significantly impact risk for allergic disease.
Our long term goal is to identify mechanisms for opposing functions of two forms of vitamin E, alpha-tocopherol and gamma-tocopherol, in the development of allergic responses. As a step towards our long-term goal, our central hypothesis is that early in life, alpha-tocopherol reduces and gamma-tocopherol elevates 1) allergic responses and 2) development of a subset of dendritic cells critical for the initiation of allergic inflammation. Completion of these studies will have significant impact on our understanding of mechanisms of alpha- tocopherol and gamma-tocopherol regulation of dendritic cells during development of allergies, on design of clinical studies with forms of vitamin E and on risk for allergic disease in future generations.
| Abdala-Valencia, Hiam; Kountz, Timothy S; Marchese, Michelle E et al. (2018) VCAM-1 induces signals that stimulate ZO-1 serine phosphorylation and reduces ZO-1 localization at lung endothelial cell junctions. J Leukoc Biol 104:215-228 |
