IL-16 is a pleiotropic cytokine which has been associated with allergic airway inflammation in humans and mice. It is constitutively synthesized by T-cells and is induced in the bronchial epithelium in allergic inflammation. The role of IL-16 as a CD4 ligand has been extensively studied. Stimulation of CD4+ T-cells with IL-16 results in phosphorylation of p56lck,expression of IL-2R-alpha and beta, and chemotaxis. IL-16 also downregulates TCR/CD3 mediated T-cell activation: it inhibits the mixed lymphocyte reaction, renders Tcells anergic, and abrogates activation by anti-CD3 stimulation. In murine models of allergic inflammation IL-16 downregulates antigen-driven T-cell activation. In these animal studies exogenous or transgenically expressed airway IL-16 decreases airway hyperresponsiveness (AHR) and eosinophilia, cardinal features of TH2 responses. This proposal is designed to elucidate the paracrine and autocrine effects of CD4+ T-cell derived IL-16 on allergic airway inflammation. We hypothesize that CD4+ T-cell IL-16 will inhibit antigen recognition by naive and sensitized T-cells; and that the effects of IL-16 are selective for TH2-mediated inflammation. I propose to use experimental models of allergic inflammation and bone marrow chimeras with knockout and transgenic mice to address the role of CD4+ T-cell IL-16 in the murine allergic airway response. Specifically, this proposal will address two major questions: 1) What is the contribution of T-cell derived IL-16 in the modulation of airway inflammation in TH2 cytokine overexpression and allergen exposure models of allergic airway inflammation? 2) What phases of the T cell immune response does IL-16 inhibit? These questions will be addressed by examining markers of T-cell activation in the lymph nodes and lung, antigen-specific immunoglobulins, airway inflammation and AHR in a murine model of allergic airway inflammation. These studies will provide direct training in transgenic technology, generation of bone marrow chimeric mice and manipulation of TH1 vs. TH2 responses and broader insights into the role of IL-16 in the allergic response.
| Summer, R; Little, F F; Ouchi, N et al. (2008) Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice. Am J Physiol Lung Cell Mol Physiol 294:L1035-42 |
