| IL-27/IFN-γ induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages. | |
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MedLine Citation:
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PMID: 20817868 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Inflammation and airway hyperresponsiveness (AHR) are hallmark features of asthma and often correlate with the severity of clinical disease. Although these features of asthma can be effectively managed with glucocorticoid therapy, a subgroup of patients, typically with severe asthma, remains refractory to therapy. The mechanisms leading to steroid resistance in severe asthmatics are poorly understood but may be related to the activation of innate host defense pathways. Previously, we have shown that IFN-γ-producing cells and LPS, two factors that are associated with severe asthma, induce steroid-resistant AHR in a mouse model. We now demonstrate that cooperative signaling induced by IFN-γ and LPS results in the production of IL-27 by mouse pulmonary macrophages. IL-27 and IFN-γ uniquely cooperate to induce glucocorticoid-resistant AHR through a previously unknown MyD88-dependent mechanism in pulmonary macrophages. Importantly, integrated signaling by IL-27/IFN-γ inhibits glucocorticoid-induced translocation of the glucocorticoid receptor to the nucleus of macrophages. Furthermore, expression of both IL-27 and IFN-γ was increased in the induced sputum of steroid-refractory asthmatics. These results suggest that a potential mechanism for steroid resistance in asthma is the activation of MyD88-dependent pathways in macrophages that are triggered by IL-27 and IFN-γ, and that manipulation of these pathways may be a therapeutic target. |
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Authors:
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Jing Jing Li; Wan Wang; Katherine J Baines; Nikola A Bowden; Philip M Hansbro; Peter G Gibson; Rakesh K Kumar; Paul S Foster; Ming Yang |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-03 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 185 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-22 Completed Date: 2010-10-19 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 4401-9 Citation Subset: AIM; IM |
Affiliation:
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Centre for Asthma and Respiratory Disease, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Asthma / immunology, metabolism Bronchial Hyperreactivity / immunology, metabolism* Cell Separation Enzyme-Linked Immunosorbent Assay Flow Cytometry Fluorescent Antibody Technique Glucocorticoids / metabolism* Humans Interferon-gamma / immunology, metabolism* Interleukins / immunology, metabolism* Macrophage Activation / immunology Macrophages, Alveolar / immunology, metabolism* Mice Mice, Inbred BALB C Mice, Knockout Myeloid Differentiation Factor 88 / immunology, metabolism* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / immunology |
| Chemical | |
Reg. No./Substance:
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0/Glucocorticoids; 0/Il27 protein, mouse; 0/Interleukins; 0/Myd88 protein, mouse; 0/Myeloid Differentiation Factor 88; 82115-62-6/Interferon-gamma |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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