Abstract
The closely related Th2 cytokines, IL-4 and IL-13, share many biological functions that are considered important in the development of allergic airway inflammation and airway hyperresponsiveness (AHR). The overlap of their functions results from the IL-4R alpha-chain forming an important functional signaling component of both the IL-4 and IL-13 receptors. Mutations in the C terminus region of the IL-4 protein produce IL-4 mutants that bind to the IL-4R alpha-chain with high affinity, but do not induce cellular responses. A murine IL-4 mutant (C118 deletion) protein (IL-4R antagonist) inhibited IL-4- and IL-13-induced STAT6 phosphorylation as well as IL-4- and IL-13-induced IgE production in vitro. Administration of murine IL-4R antagonist during allergen (OVA) challenge inhibited the development of allergic airway eosinophilia and AHR in mice previously sensitized with OVA. The inhibitory effect on airway eosinophilia and AHR was associated with reduced levels of IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid as well as reduced serum levels of OVA-IGE: These observations demonstrate the therapeutic potential of IL-4 mutant protein receptor antagonists that inhibit both IL-4 and IL-13 in the treatment of allergic asthma.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibody Specificity
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B-Lymphocyte Subsets / immunology
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Bronchial Hyperreactivity / immunology
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Bronchial Hyperreactivity / pathology
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Bronchial Hyperreactivity / prevention & control*
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Bronchoalveolar Lavage Fluid / cytology
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Bronchoalveolar Lavage Fluid / immunology
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Cells, Cultured
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Cytokines / antagonists & inhibitors
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Cytokines / metabolism
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Down-Regulation / genetics
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Down-Regulation / immunology
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Eosinophils / immunology
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Eosinophils / pathology
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Epithelium / immunology
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Epithelium / metabolism
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Female
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Humans
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Immunoglobulin E / biosynthesis
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Immunophenotyping
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Immunosuppressive Agents / administration & dosage*
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Immunosuppressive Agents / chemical synthesis
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Immunosuppressive Agents / pharmacology
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Injections, Intraperitoneal
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Injections, Subcutaneous
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Interleukin-13 / antagonists & inhibitors*
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Interleukin-13 / pharmacology
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Interleukin-4 / antagonists & inhibitors*
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Interleukin-4 / genetics
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Interleukin-4 / pharmacology
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Leukocyte Count
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Lung / immunology
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Lung / pathology
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Inbred BALB C
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Mucus / metabolism
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Ovalbumin / administration & dosage
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Ovalbumin / immunology*
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Phosphorylation
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Pulmonary Eosinophilia / immunology
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Pulmonary Eosinophilia / pathology
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Pulmonary Eosinophilia / prevention & control*
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Receptors, Interleukin-4 / antagonists & inhibitors*
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Recombinant Proteins / administration & dosage*
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Recombinant Proteins / chemical synthesis
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Recombinant Proteins / pharmacology
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STAT6 Transcription Factor
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Spleen / cytology
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Spleen / immunology
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T-Lymphocyte Subsets / immunology
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / metabolism
Substances
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Cytokines
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Immunosuppressive Agents
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Interleukin-13
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Receptors, Interleukin-4
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Recombinant Proteins
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STAT6 Transcription Factor
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STAT6 protein, human
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Stat6 protein, mouse
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Trans-Activators
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Interleukin-4
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Immunoglobulin E
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Ovalbumin