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

Journal article
Authors Malin Erlandsson
Sofia Silfverswärd Lindblad
Mitra Nadali
Minna Turkkila
Mattias Svensson
Ing-Marie Jonsson
Karin Andersson
Maria Bokarewa
Published in Biochimica et Biophysica Acta - Molecular basis of disease
Volume 1863
Issue 9
Pages 2158-2170
ISSN 0005-2728
Publication year 2017
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Pages 2158-2170
Language en
Links dx.doi.org/10.1016/j.bbadis.2017.06...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Rheumatology and Autoimmunity, Immunology in the medical area

Abstract

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.In the present study, we assess if disruption of IGF-1R signalling resolves arthritis.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.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.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.

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