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SAT0026 Signalling through insulin-like growth factor 1 receptor contributes to il-6 production and supports t cell dependent inflammation in rheumatoid arthritis
  1. M Erlandsson1,
  2. M Nadali2,
  3. S Silfverswärd Töyrä2,
  4. MN Svensson2,
  5. I-M Jonsson2,
  6. KM Andersson3,
  7. MI Bokarewa2
  1. 1Rheumatology and Inflammation Research
  2. 2Dept of Rheumatology and Inflammation Research
  3. 3Dept. of Rheumatology and Inflammation Research, Gothenburg University, Gothenburg, Sweden

Abstract

Background Insulin-like growth factor (IGF) 1 receptor is essential for cell energy metabolism. It plays a key role linking glucose and lipid metabolism of active cells and may turn pathogenic in uncontrolled tissue growth in tumours. In rheumatoid arthritis (RA), the IGF-1R signalling is activated supporting expansion of the inflamed synovia.

Objectives The aim of the present study was to understand the place of IGF-1R expression and signalling for development of adaptive immune responses in the setting of prospective RA cohort and in experimental arthritis.

Methods Clinical associations of IGF1R expression in leukocytes of the peripheral blood were studied in 84 female RA patients with mean disease duration 8 years, all treated with methotrexate. Consequences of the IGF1R signalling inhibition for arthritis were studied in mBSA immunised Balb/c mice treated with NT157 compound promoting degradation of the insulin receptor substrates IRS-1/2.

Results In RA patients, high expression of IGF1R in leukocytes was associated with systemic inflammation as verified by higher transcription factor NF-kB (p=0.033), serum levels of IL-6 (p=0.006) and erythrocyte sedimentation rate (p=0.003), and higher pain perception (VAS, p=0.019). Additionally, women with high IGF1R were often in need of combined DMARD treatment (p=0.045). Phosphorylated IGF1R and STAT3 enrich T cells infiltrate in RA synovia. Treatment with NT157 rendered no metabolic consequences to mouse body weight and serum glucose levels. NT157 inhibited the phosphorylation of IGF1R and STAT3 in synovia, and alleviated arthritis and erosions in mice. It also reduced IGF1R+ T cell population in spleen and despaired ERK and Akt signalling. This limited the ability of mBSA-specific T cells to produce IL-6 (p=0.013), IFNg (p=0.024) and IL-17 (p=0.0097). The reduction of IL-6 and IL-17 levels was associated with changed RoRgt/FoxP3 balance.

Conclusions IGF1R signalling contributes to severe RA by triggering T cell dependent inflammation in arthritis. Inhibition of IGF1R on the level of insulin receptor substrates alleviates arthritis by restricting IL-6 dependent formation of Th17 cells and may open for new treatment strategies in RA.

Disclosure of Interest None declared

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