CYTOKINE REGULATION OF A MOUSE MODEL OF ASTHMA

University Of Cincinnati, Cincinnati OH

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Abstract

Asthma affects 3-6% of the general population of the United States and is an increasingly common cause of morbidity and mortality. The cytokine IL-4 has a central role in the pathogenesis of this disease: it stimulates the production of IgE and mucus, attracts eosinophils and other inflammatory cells to the lungs, stimulates the production of other asthma-associated cytokines, and, as shown by our preliminary data, increases smooth muscle responsiveness to cholinergic stimulation. This proposal will investigate the relative roles of the two receptors that bind IL-4 (the IL-4 receptor and the IL-13 receptors, in these processes. We will determine the mechanisms by which IL-4 and IL-13 attract eosinophils to the lungs, the mechanism by which TGF-alpha acts synergistically with IL-4 to induce pulmonary eosinophilia and the mechanism by which IL-12 inhibits IL-4 induced pulmonary eosinophilia. In addition, we will perform experiments that investigate a noel observation that chronic exposure to IL-4 inhibits in vitro cyclic AMP responsiveness of pulmonary cell membranes to beta-adrenergic stimulation, to determine whether IL-4 similarly induces decreased pulmonary responsiveness to beta2-adrenergic stimulation in intact animals, whether this decrease in beta-adrenergic responsiveness can be induced also be allergen inhalation, whether this effect of IL-4 is also induced by IL-13, whether it is mediated by Stat6 signaling, whether it is associated with decreased pulmonary beta2-adrenergic receptor expression, whether it can be induced by other cytokines that enhance responsiveness to cholinergic stimulation, whether it requires the presence of inflammatory cells, and whether it is enhanced by TGF-alpha and opposed by IL-12. Our proposed studies will use transgenic mouse strains that over-express IL-4 in their lungs and that vary in their expression of IL-5, Stat6, and the IL-4 and IL-13 receptors; long acting forms of IL-4 and TGF-alpha that are administered nasally or systematically, and neutralizing antibodies specific for IL-4, the IL-4 receptor, and the IL-13 receptor. Pulmonary inflammation will be evaluated by microscopic examination of bronchoalveolar lavage cells and lung sections. In vitro assays will measure beta2-adrenergic receptor concentration and responsiveness in lung cell membranes, while responsiveness of intact mice to cholinergic and beta2-adrenergic stimulation will be determined by non-invasive barometric plethysmography with a Buxco apparatus. By clarifying the mechanisms by which cytokines induce pulmonary inflammation and airway responsiveness, the proposed studies will provide information important for rational therapy for asthma.