Although IL-13 and IL-4 both induce features of asthma in mice by binding to the type 2 IL-4 receptor and activating Stat6, IL-13 has a greater role than IL-4 in the development of airway hyperresponsiveness (AHR) in mouse models of allergen-induced asthma. We will test the hypothesis that this greater role reflects both greater production of IL-13 than IL-4 and unique IL-13 effects. Greater production of IL-13 cannot, by itself, account for the development of AHR, pulmonary fibrosis, and emphysema in mice that express an IL-13 transgene with a lung-specific promoter, but not in mice that express an IL-4 transgene with the same promoter. This observation suggests a qualitative difference in the abilities of IL-13 vs. IL-4 to induce pulmonary pathology. Studies in mice inoculated intra-tracheally with IL-4 vs. IL-13 support this possibility by demonstrating that IL-13 is more potent than IL-4 at inducing and maintaining AHR; that IL-13 induces the expression of 4 genes in the lungs that are induced little, if at all, by IL-4; and that optimal induction of AHR in allergen-inoculated mice requires IL-13Ralpha2, a protein that binds IL-13 but not IL-4. This proposal will investigate why IL-13 contributes more than IL-4 to AHR in mouse models of asthma. We will: 1) compare in vivo production of free and soluble receptor-complexed IL-4 vs. IL-13 production in allergen-induced models of asthma; 2) evaluate the relative potencies of free and soluble-receptor complexed IL-4 vs. IL-13 in the induction of AHR; 3) determine the Stat6-dependence the """"""""IL-13-specific"""""""" genes; 4) determine whether IL-4 suppresses pulmonary effects of IL-13; 5) evaluate whether IL-13 can signal through a unique receptor that is not activated by IL-4; 6) determine whether IL-4 and IL-13 have different effects on the expression of receptor molecules that can influence signaling by these cytokines; and 7) identify the pulmonary cell type(s) that express the """"""""IL-13-specific"""""""" genes and are involved in induction and maintenance of AHR by IL-4 and IL-13. Experiments performed will feature the use of a novel assay system for in vivo cytokine production; measurement of AHR by invasive and non-invasive techniques; measurement of gene expression by real-time PCR; and the use of several sets of transgenic mice, including mice that overexpress IL-4 and/or IL-13 in their lungs, mice that express the type 2, but not the type 1 IL-4R, mice that lack or overexpress IL-13Ralpha2, mice that fall to express Stat6, mice that selectively express IL-4Ralpha (a component of the IL-4 and IL-13 receptors) on single cell types in the lungs, and mice that selectively fail to express IL-4Ralpha on selected cell types in the lungs. Results of these experiments should promote the development of new treatments of human asthma by defining the mechanisms by which IL-13 has its unique effects on the lungs.
Showing the most recent 10 out of 56 publications
