A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma - 30/01/13
Corresponding author: Sarah Spiegel, PhD, Virginia Commonwealth University, School of Medicine, Department of Biochemistry and Molecular Biology, Box 980614, Richmond, VA 23298-0614.Abstract |
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-⍺ 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.
Le texte complet de cet article est disponible en PDF.Key words : Sphingosine-1-phosphate, sphingosine kinase, mast cells, nuclear factor κB, airway hyperresponsiveness, asthma
Abbreviations used : AHR, BAL, BMMC, IκB⍺, IKK, NF-κB, OVA, S1P, SphK
Plan
| Supported by National Institutes of Health (NIH) grants RO1AI50094 and U19AI077435 (to S.S.) and K01AR053186 (to C.A.O.). The Virginia Commonwealth University microscopy core laboratory is supported in part by the NIH/NINDS center core grant 5P30NS047463. |
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| Disclosure of potential conflict of interest: J. C. Allegood has received grants from the National Institutes of Health. S. Spiegel and D. Conrad have received grants from the Asthma and Allergic Diseases Cooperative Research Centers. J. J. Ryan has received grants from the National Institutes of Health. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 2
P. 501 - février 2013 Retour au numéro
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