Abstract
Mucus hyperproduction in asthma results from airway inflammation and contributes to clinical symptoms, airway obstruction and mortality. Th2 lymphocytes and eosinophils dominate the airway inflammatory infiltrate. We investigated the role of different lymphocyte subsets and their cytokines in the stimulation of mucus production using a system in which T cell receptor (TCR) transgenic CD4+ Th cells were generated in vitro, transferred into recipient mice and activated in the respiratory tract with inhaled antigen. Th2 cells induced mucus production and eosinophilic inflammation, while mice that received Th1 cells exhibited airway inflammation without mucus. Th1 cells failed to stimulate mucus due to the inhibitory effects of interferon (IFN)gamma. Mucus was induced by Th2 cells in the absence of interleukin (IL)4, IL5, eosinophils and mast cells, but not without IL4R alpha signalling. Th2 cells lacking IL13 could not stimulate mucus production, despite the presence of airway inflammation. IL9 also stimulates mucus through an IL13-mediated pathway. Using bone marrow chimeras we show that IL13 acts on structural cells in the lung, most likely by direct stimulation of epithelial cells, and not through intermediate inflammatory cells. In asthma, airway inflammation with CD4+ Th2 cells stimulates mucus production by a single pathway mediated by IL13.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Administration, Inhalation
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Animals
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Asthma / immunology
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Asthma / physiopathology*
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Bronchoalveolar Lavage Fluid / chemistry
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Bronchoalveolar Lavage Fluid / cytology
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Cells, Cultured / transplantation
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Exocytosis
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Gene Expression Regulation / drug effects*
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Immunization
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Interferon-gamma / physiology
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Interferons / drug effects
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Interferons / physiology
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Interleukin-13 / deficiency
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Interleukin-13 / physiology*
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Interleukin-13 Receptor alpha1 Subunit
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Interleukin-4 / biosynthesis
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Interleukin-4 / physiology
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Interleukin-5 / deficiency
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Interleukin-5 / physiology
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Interleukin-9 / physiology
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Mast Cells / pathology
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Mice
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Mice, Transgenic
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Models, Animal
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Mucins / biosynthesis*
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Mucins / genetics
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Mucus / metabolism*
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Ovalbumin / administration & dosage
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Ovalbumin / immunology
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology
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Pulmonary Eosinophilia / etiology*
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Pulmonary Eosinophilia / pathology
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Radiation Chimera
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Receptors, Antigen, T-Cell, alpha-beta / genetics*
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Receptors, Interleukin / physiology
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Receptors, Interleukin-13
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Receptors, Interleukin-4 / deficiency
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Receptors, Interleukin-4 / physiology*
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Respiratory System / immunology
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Respiratory System / metabolism*
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Signal Transduction
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Th1 Cells / physiology
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Th1 Cells / transplantation
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Th2 Cells / metabolism*
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Th2 Cells / transplantation
Substances
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Il13ra1 protein, mouse
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Interleukin-13
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Interleukin-13 Receptor alpha1 Subunit
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Interleukin-5
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Interleukin-9
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Mucins
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OVA 323-339
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Peptide Fragments
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Interleukin
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Receptors, Interleukin-13
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Receptors, Interleukin-4
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Interleukin-4
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Interferon-gamma
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Ovalbumin
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Interferons