Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 131, Issue 2, Pages 501-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2012.07.014
Keywords
Sphingosine-1-phosphate; sphingosine kinase; mast cells; nuclear factor kappa B; airway hyperresponsiveness; asthma
Categories
Funding
- National Institutes of Health (NIH) [RO1AI50094, U19AI077435, K01AR053186]
- NIH/NINDS center core grant [5P30NS047463]
- National Institutes of Health
- Asthma and Allergic Diseases Cooperative Research Centers
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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 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 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-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. Conclusion: S1P and SphK1 play important roles in mast cell-dependent, OVA-induced allergic inflammation and AHR, in part by regulating the NF-kappa B pathway. (J Allergy Clin Immunol 2013;131:501-11.)
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