Direct IL-4 and IL-13 effects on pulmonary smooth muscle in allergic airway disea

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

DESCRIPTION (provided by applicant): Development of allergic airway disease in mice depends on IL-4R1-mediated activation of Stat6 by IL-4 and IL- 13, with the latter cytokine being more important than the former during the effector phase of disease. We have evaluated the cell types through which IL-4 and IL-13 contribute to allergic airway disease and explored mechanisms responsible for the greater effects of IL-13. Results show that: 1) inhaled IL-4 and IL-13 can each independently induce airway hyperresponsiveness (AHR) in mice through direct effects on airway smooth muscle cells;2) AHR is induced independently of eosinophilia and goblet cell hyperplasia;3) induction of AHR by IL-4 and IL-13 requires signaling through the type 2 IL-4R;4) IL-4, but not IL-13, induces increased secretion of IFN-3 and IL-10, cytokines that can suppress allergic airway disease;5) IL-4 signaling through the type 1 IL-4R suppresses the expression of some of the genes induced in the lungs by IL-13;and 6) IL-13 suppresses expression of miR-1, a microRNA expressed in muscle that suppresses translation of multiple genes that promote differentiation, proliferation and responsiveness. Concurrent studies by other investigators have shown that: 1) IL-13 can induce AHR through direct effects on pulmonary epithelium, but also induces AHR in mice whose pulmonary epithelium cannot directly respond to this cytokine;and 2) the type 2 IL-4R binds IL-13 differently and with greater affinity than it binds IL-4. Taken together, these observations suggest our 3 central hypotheses: 1) induction of AHR by IL-4 and IL-13 is completely accounted for by their effects on smooth muscle and airway epithelium;2) IL-4/IL-13-induced changes in smooth muscle gene transcription and translation contribute to the effects of these cytokines on airway responsiveness and muscle remodeling and 3) the greater ability of inhaled IL-13 than IL-4 to increase AHR in mice results from IL-4 activation of the type 1 IL-4 receptor (IL-4R), with consequent production of IFN-3 and IL-10, rather than from differences in IL-4 vs. IL- 13 signaling through the type 2 IL-4R or IL-13R12. These hypotheses will be tested by 4 specific aims: 1. Determine whether IL-13 induction of AHR is prevented by deleting IL-4R1 from both smooth muscle and epithelial cells. 2. Compare development of chronic airway remodeling in mice that overexpress IL-4 or IL-13 in their lungs and selectively express IL-4R1 on smooth muscle or pulmonary epithelium. 3. Evaluate the effects of miR-1 downregulation on airway responsiveness and Identify genes that are up- or downregulated by IL-4 and IL-13 on airway smooth muscle cells. 4. Determine whether induction of IFN-3 and/or IL-10 by IL-4 contributes to the stronger induction of AHR by IL-13. Proposed experiments will use transgenic mice, recombinant cytokines, monoclonal antibodies, cell transfer systems, assays of in vivo cytokine production, flow cytometry and 3 different techniques for measuring airway responsiveness to test our hypothesis. Results should improve understanding of asthma pathogenesis, provide a model that can be used for in vivo tests of agents that may regulate smooth muscle-dependent AHR in human asthma and provide information that should guide the choice of IL-13 vs. IL-4R antagonists as potential asthma therapeutics. PUBLIC HEALTH RELEVANCE: Asthma, a chronic lung disease characterized by airway smooth muscle hyperplasia and hyperresponsiveness, affects more than 7% of Americans and has been increasing in incidence for the past 50 years. Two cytokines, IL-4 and IL-13, induce acute and chronic changes in pulmonary structure and function that contribute to airway hyperresponsiveness. However, mechanisms responsible for IL-4- and IL-13-induced changes in smooth muscle structure and function that contribute to airway hyperresponsiveness are poorly understood, as are mechanisms that account for differences in the effects of IL-4 vs. IL-13. Proposed studies with a mouse model in which airway hyperresponsiveness is induced solely by direct IL-4 and IL-13 effects on smooth muscle should help to elucidate these mechanisms and may reveal new approaches for asthma therapy.