Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis.
Arthritis Rheum
; 60(9): 2782-93, 2009 Sep.
Article
en En
| MEDLINE
| ID: mdl-19714583
ABSTRACT
OBJECTIVE:
Systemic-onset juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by arthritis and systemic features. Its pathogenesis is still largely unknown. It is characterized immunologically by natural killer (NK) cell dysfunction and cytokine signatures that predominantly feature interleukin-1 (IL-1), IL-6, and IL-18. Since IL-18 can drive NK cell function, we examined how the high plasma levels of this cytokine are related to the documented NK cell failure in these patients.METHODS:
The phenotype and function of NK cells from 10 healthy control subjects, 15 patients with polyarticular JIA, and 15 patients with systemic-onset JIA were characterized by staining and functional assays in vitro. IL-18 ligand binding was visualized by fluorescence microscopy. Phosphorylation of several MAP kinases and the IL-18 receptor beta (IL-18Rbeta) were visualized by Western blotting.RESULTS:
IL-18 from the plasma of systemic-onset JIA patients stimulated the activation of NK cells from healthy controls and bound its cognate receptor. However, NK cells from systemic-onset JIA patients failed to up-regulate cell-mediated killing molecules, such as perforin and interferon-gamma, after IL-18 stimulation. Furthermore, treatment with IL-18 did not induce the phosphorylation of receptor-activated MAP kinases in NK cells. Alternate activation of NK cells by IL-12 induced NK cell cytotoxicity. We observed no additive effect of IL-18 in combination with IL-12 in systemic-onset JIA patients. Immunoprecipitation of IL-18Rbeta showed that NK cells from systemic-onset JIA could not phosphorylate this receptor after IL-18 stimulation.CONCLUSION:
The mechanism of the impaired NK cell function in systemic-onset JIA involves a defect in IL-18Rbeta phosphorylation. This observation has major implications for the understanding and, ultimately, the treatment of systemic-onset JIA.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Artritis Juvenil
/
Células Asesinas Naturales
/
Subunidad beta del Receptor de Interleucina-18
Tipo de estudio:
Etiology_studies
/
Observational_studies
Límite:
Adolescent
/
Child
/
Child, preschool
/
Female
/
Humans
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Infant
/
Male
Idioma:
En
Revista:
Arthritis Rheum
Año:
2009
Tipo del documento:
Article
País de afiliación:
Países Bajos