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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-A (02))
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Banks-Schlegel, Susan P
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Cincinnati Children's Hospital Medical Center
United States
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