Artículo
A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent mouse model of allergic asthma
Price, Megan M.; Oskeritzian, Carole A.; Falanga, Yves T.; Harikumar, Kuzhuvelil B.; Allegood, Jeremy C.; Alvarez, Sergio Eduardo
; Conrad, Daniel; Ryan, John J.; Milstien, Sheldon; Spiegel, Sarah
Fecha de publicación:
02/2013
Editorial:
Elsevier
Revista:
Journal of Allergy and Clinical Immunology
ISSN:
0091-6749
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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 cells 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-kB (NF-kB), 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-g, and TNF-a and the chemokines eotaxin and CCL2 in bronchoalveolar lavage fluid; and decreased pulmonary inflammation, as well as activation of NF-kB in the lungs.
Palabras clave:
Sphingosine-1-Phosphate
,
Inflammation
,
Chemokines
,
Asthma
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Articulos(IMIBIO-SL)
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Citación
Price, Megan M.; Oskeritzian, Carole A.; Falanga, Yves T.; Harikumar, Kuzhuvelil B.; Allegood, Jeremy C.; et al.; A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent mouse model of allergic asthma; Elsevier; Journal of Allergy and Clinical Immunology; 131; 2; 2-2013; 501-511.e1
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