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Biochim Biophys Acta Mol Basis Dis. 2017 Sep;1863(9):2158-2170. doi: 10.1016/j.bbadis.2017.06.002. Epub 2017 Jun 3.

IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis.

Author information

1
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden.
2
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna Stråket 12, 41346 Gothenburg, Sweden.
3
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna Stråket 12, 41346 Gothenburg, Sweden. Electronic address: maria.bokarewa@rheuma.gu.se.

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 AND METHODS:

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.

KEYWORDS:

IL6; Insulin receptor substrate; Insulin-like growth factor receptor; Rheumatoid arthritis; Th17

PMID:
28583713
DOI:
10.1016/j.bbadis.2017.06.002
[Indexed for MEDLINE]
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