IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis.
Biochim Biophys Acta Mol Basis Dis
; 1863(9): 2158-2170, 2017 09.
Article
em En
| MEDLINE
| ID: mdl-28583713
ABSTRACT
BACKGROUND:
Signalling through insulin-like growth factor 1 receptor (IGF-1R) is essential for cell survival, but may turn pathogenic in uncontrolled tissue growth in tumours. In rheumatoid arthritis (RA), the IGF-1R signalling is activated and supports expansion of the inflamed synovia.AIM:
In the present study, we assess if disruption of IGF-1R signalling resolves arthritis. MATERIAL ANDMETHODS:
Clinical associations of IGF-1R expression in leukocytes of the peripheral blood were studied in 84 RA patients. Consequences of the IGF-1R signalling inhibition for arthritis were studied in mBSA immunised Balb/c mice treated with NT157 compound promoting degradation of insulin receptor substrates.RESULTS:
In RA patients, high expression of IGF-1R in leukocytes was associated with systemic inflammation as verified by higher expression of NF-kB, serum levels of IL6 and erythrocyte sedimentation rate, and higher pain perception. Additionally, phosphorylated IGF-1R and STAT3 enriched T cells infiltrate in RA synovia. Treatment with NT157 inhibited the phosphorylation of IGF-1R and STAT3 in synovia, and alleviated arthritis and joint damage in mice. It also reduced expression of IGF-1R and despaired ERK and Akt signalling in spleen T cells. This limited IL-6 production, changed RoRgt/FoxP3 balance and IL17 levels.CONCLUSION:
IGF-1R signalling contributes to T cell dependent inflammation in arthritis. Inhibition of IGF-1R on the level of insulin receptor substrates alleviates arthritis by restricting IL6-dependent formation of Th17 cells and may open for new treatment strategies in RA.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
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Membrana Sinovial
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Transdução de Sinais
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Interleucina-6
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Receptor IGF Tipo 1
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Células Th17
Limite:
Adult
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Animals
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Humans
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Middle aged
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article