A major overall aim of this SCOR proposal is to understand how inflammatory cells infiltrate the pulmonary airway in asthma. In that context, interleukin-4 (IL-4) appears to be one of the critical factors regulating immune cell recruitment from the circulation as well as subsequent immune cell differentiation and activation. IL-4 acts on T cells and B cells to direct differentiation and can act in concert with other cytokines (notably IL-3) to cause full expression of allergic inflammation. IL-4 is also a key determinant for inducing cell adhesion molecules (notably VCAM-I) on the endothelial cell surface, and this effect may mediate recruitment of alpha4beta1-bearing immune cells, such as T cells, eosinophils, and macrophages. These IL-4- driven events appear to be key features of asthma because immune- cell IL-4 and endothelial-cell VCAM-l are increased in tissue from asthmatic subjects and antigen-induced airway inflammation is blocked in animals lacking the IL-4 gene or treated with anti- VCAM-I antibodies. We therefore reasoned that the control of IL-4 production is critical for regulating the development of airway inflammation in allergic asthma. Although several airway cell types are capable of producing IL-4, we have focused our work on the antigen- specific T cell. In murine models of T cell behavior, the principal subset of antigen-specific T cells that secrete IL-4 is termed T helper (Th) type 2. The Th2-type T cells have the potential to reinforce the allergic character of pulmonary immune response, because one action of IL-4 is to induce further Th2 development. As an amplifier of this cycle of allergic inflammation, the Th2 cell also represents a therapeutic target of potential significance. Accordingly, this project aims at determining the molecular controls for IL-4 generation and consequent IL-4 action. Our previous studies identified elements of the IL-4 gene promoter that mediate DNA/protein interactions critical for gene activation. Further, we have demonstrated the roles of IL-4 and IL-12 on T helper cell development and IL-4 production using transgenic mouse models of T cell behavior. We take advantage of our extensive definition of IL-4 biology in murine Th2-type T cells to define: (i) the role of a newly- identified transcription factor (designated Stat6) in controlling IL-4 gene activation; and (ii) the critical interaction of the IL- 4-dependent activity with the action of IL-12. We will then extend these findings to studies of T cells obtained from nonasthmatic and asthmatic subjects to pinpoint molecular abnormalities in IL-4 generation and action that may be responsible for the development of airway inflammation.
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