Journal of allergy and clinical immunology, 2013-02, Vol.131 (2), p.501-511.e1
2013
Details
- Autor(en) / Beteiligte
- Titel
- A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma
- Ist Teil von
- Journal of allergy and clinical immunology, 2013-02, Vol.131 (2), p.501-511.e1
- Ort / Verlag
- New York, NY: Elsevier
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Background Sphingosine-1-phosphate (S1P), which is produced by 2 sphingosine kinase (SphK) isoenzymes, SphK1 and SphK2, has been implicated in IgE-mediated mast cell responses. However, studies of allergic inflammation in isotype-specific SphK knockout mice have not clarified their contribution, and the role that S1P plays in vivo in a mast cell– and IgE-dependent murine model of allergic asthma has not yet been examined. Objective We used an isoenzyme-specific SphK1 inhibitor, SK1-I, to investigate the contributions of S1P and SphK1 to mast cell–dependent airway hyperresponsiveness (AHR) and airway inflammation in mice. Methods Allergic airway inflammation and AHR were examined in a mast cell–dependent murine model of ovalbumin (OVA)–induced asthma. C57BL/6 mice received intranasal delivery of SK1-I before sensitization and challenge with OVA or only before challenge. Results SK1-I inhibited antigen-dependent activation of human and murine mast cells and suppressed activation of nuclear factor κB (NF-κB), a master transcription factor that regulates the expression of proinflammatory cytokines. SK1-I treatment of mice sensitized to OVA in the absence of adjuvant, in which mast cell–dependent allergic inflammation develops, significantly reduced OVA-induced AHR to methacholine; decreased numbers of eosinophils and levels of the cytokines IL-4, IL-5, IL-6, IL-13, IFN-γ, and TNF-α and the chemokines eotaxin and CCL2 in bronchoalveolar lavage fluid; and decreased pulmonary inflammation, as well as activation of NF-κB in the lungs. Conclusion S1P and SphK1 play important roles in mast cell–dependent, OVA-induced allergic inflammation and AHR, in part by regulating the NF-κB pathway.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0091-6749eISSN: 1097-6825DOI: 10.1016/j.jaci.2012.07.014Titel-ID: cdi_proquest_journals_1644750636
- Format
- –
- Schlagworte
- Allergies, Allergy and Immunology, Amino Alcohols - pharmacology, Animals, Asthma, Asthma - chemically induced, Asthma - drug therapy, Asthma - enzymology, Asthma - metabolism, Biological and medical sciences, Bronchial Hyperreactivity - drug therapy, Bronchial Hyperreactivity - enzymology, Bronchial Hyperreactivity - metabolism, Bronchial Hyperreactivity - pathology, Bronchoalveolar Lavage Fluid - chemistry, Cells, Cultured, Chemokine CCL2 - metabolism, Chronic obstructive pulmonary disease, asthma, Cytokines, Female, Fundamental and applied biological sciences. Psychology, Fundamental immunology, Goblet Cells - drug effects, Goblet Cells - metabolism, Humans, Hyperplasia - drug therapy, Hyperplasia - metabolism, Immunoglobulin E - metabolism, Immunopathology, Inflammation - drug therapy, Inflammation - metabolism, Interferon-gamma - metabolism, Interleukins - metabolism, Kinases, Laboratory animals, Lung - drug effects, Lung - metabolism, Lungs, Lysophospholipids - metabolism, Mast Cells - drug effects, Mast Cells - metabolism, Medical sciences, Methacholine Chloride - pharmacology, Mice, Mice, Inbred C57BL, NF-kappa B - metabolism, Ovalbumin - pharmacology, Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors, Phosphotransferases (Alcohol Group Acceptor) - metabolism, Pneumology, Rodents, Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis, Sphingosine - analogs & derivatives, Sphingosine - metabolism, Studies, Tumor Necrosis Factor-alpha - metabolism