Raf kinase inhibitor protein negatively regulates FcεRI-mediated mast cell activation and allergic response.
Proc Natl Acad Sci U S A
; 115(42): E9859-E9868, 2018 10 16.
Article
em En
| MEDLINE
| ID: mdl-30282734
ABSTRACT
The signaling cascades triggered by the cross-linkage of immunoglobulin E (IgE) with its high-affinity receptor (FcεRI) on mast cells contribute to multiple allergic disorders, such as asthma, rhinitis, and atopic dermatitis. Restraint of intracellular signals for mast cell activation is essential to restore homeostasis. In this study, we found that Raf kinase inhibitor protein (RKIP) negatively regulated mast cell activation. RKIP-deficient mast cells showed greater IgE-FcεRI-mediated activation than wild-type mast cells. Consistently, RKIP deficiency in mast cells rendered mice more sensitive to IgE-FcεRI-mediated allergic responses and ovalbumin-induced airway inflammation. Mechanistically, RKIP interacts with the p85 subunit of PI3K, prevents it from binding to GRB2-associated binding protein 2 (Gab2), and eventually inhibits the activation of the PI3K/Akt/NF-κB complex and its downstream signaling. Furthermore, the expression of RKIP was significantly down-regulated in the peripheral blood of asthma patients and in the IgE-FcεRI-stimulated mast cells. Collectively, our findings not only suggest that RKIP plays an important role in controlling mast cell-mediated allergic responses but also provide insight into therapeutic targets for mast cell-related allergic diseases.
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Base de dados:
MEDLINE
Assunto principal:
Asma
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Receptores de IgE
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Proteína de Ligação a Fosfatidiletanolamina
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Anafilaxia
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Mastócitos
Limite:
Animals
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Child
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article