A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma

• Published in: Journal of allergy and clinical immunology Vol. 131; no. 2; pp. 501 - 511.e1
• Main Authors: Price, Megan M., PhD, Oskeritzian, Carole A., PhD, Falanga, Yves T., BSc, Harikumar, Kuzhuvelil B., PhD, Allegood, Jeremy C., PhD, Alvarez, Sergio E., PhD, Conrad, Daniel, PhD, Ryan, John J., PhD, Milstien, Sheldon, PhD, Spiegel, Sarah, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 01.02.2013; Elsevier Limited
• Subjects: 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; airway hyperresponsiveness; Ovalbumin; nuclear factor κB; sphingosine kinase; SphK; Bone marrow–derived mast cell; IKK; asthma; Inhibitor of nuclear factor κB; AHR; mast cells; BAL; IκBα; IκB kinase; NF-κB; S1P; Bronchoalveolar lavage; Sphingosine-1-phosphate; OVA; BMMC; Allergy; Animal model; Hyperreactivity; Respiratory system; Respiratory tract; Immunology; Bronchus disease; Obstructive pulmonary disease; Transcription factor NFκB; Lung disease; Immunopathology; Enzyme; Respiratory disease; Transferases; Rodentia; Inflammation; Sphingosine kinase 1; Asthma; Vertebrata; Mammalia; Mouse; Kinase; Inhibitor; Mast cell
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2012.07.014

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.