IMIBIO-SL   20937
INSTITUTO MULTIDISCIPLINARIO DE INVESTIGACIONES BIOLOGICAS DE SAN LUIS
Unidad Ejecutora - UE
artículos
Título:
A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent mouse model of allergic asthma
Autor/es:
PRICE MM; OSKERITZIAN CA; FALANGA TY; HARIKUMAR KB; ALLEGOOD J; ALVAREZ SE; CONRAD D; RYAN JJ; MILSTIEN S; SPIEGEL S
Revista:
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Editorial:
MOSBY-ELSEVIER
Referencias:
Año: 2012
ISSN:
0091-6749
Resumen:
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
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.
Conclusion: S1P and SphK1 play important roles in mast cell?
dependent, OVA-induced allergic inflammation and AHR, in part by regulating the NF-kB pathway.