A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast celladependent 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, Oskeritzian, Carole A, Falanga, Yves T, Harikumar, Kuzhuvelil B, Allegood, Jeremy C, Alvarez, Sergio E, Conrad, Daniel, Ryan, John J, Milstien, Sheldon, Spiegel, Sarah
• Format: Journal Article
• Language: English
• Published: 01.02.2013
• Subjects: Adjuvants; Alveoli; Animal models; Asthma; Bronchus; Cell activation; Chemokines; eotaxin; Hypersensitivity; Inflammation; Interleukin 13; Interleukin 4; Interleukin 5; Interleukin 6; Isoenzymes; Leukocytes (eosinophilic); Lung; Mast cells; methacholine; Monocyte chemoattractant protein 1; NF- Kappa B protein; Ovalbumin; Respiratory tract; Respiratory tract diseases; Sphingosine 1-phosphate; sphingosine kinase; Transcription factors
• ISSN: 0091-6749

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 inANBvivo in a mast cella 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 celladependent airway hyperresponsiveness (AHR) and airway inflammation in mice. Methods: Allergic airway inflammation and AHR were examined in a mast celladependent murine model of ovalbumin (OVA)ainduced 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 [kappa]B (NF-[kappa]B), 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 celladependent 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-[gamma], and TNF-[alpha] and the chemokines eotaxin and CCL2 in bronchoalveolar lavage fluid; and decreased pulmonary inflammation, as well as activation of NF-[kappa]B in the lungs. Conclusions: S1P and SphK1 play important roles in mast celladependent, OVA-induced allergic inflammation and AHR, in part by regulating the NF-[kappa]B pathway.