The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17-producing cellular network at multiple sites.
Arthritis Rheum
; 64(10): 3168-78, 2012 Oct.
Article
em En
| MEDLINE
| ID: mdl-22729944
ABSTRACT
OBJECTIVE:
Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62.METHODS:
DBA/1 mice progressively display arthritis following immunization with type II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cell populations, and in situ analysis of joint inflammation in mice with CIA.RESULTS:
ES-62 was found to down-regulate IL-17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL-17 responses by targeting a complex IL-17-producing network, involving signaling between dendritic cells and γ/δ or CD4+ T cells. In addition, ES-62 directly targeted Th17 cells by down-regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL-1 and Toll-like receptor ligands. Moreover, ES-62 modulated the migration of γ/δ T cells and this was reflected by direct suppression of CD44 up-regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17-producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas.CONCLUSION:
Our findings indicate that ES-62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL-17 inflammatory network. ES-62 could be exploited in the development of novel therapeutics for RA.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Artrite Experimental
/
Células Dendríticas
/
Linfócitos T CD4-Positivos
/
Proteínas de Helminto
/
Interleucina-17
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Arthritis Rheum
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Reino Unido