IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis
| Autor: | Minna Turkkila, Karin M. E. Andersson, Mitra Nadali, Malin C. Erlandsson, Maria Bokarewa, Sofia Töyrä Silfverswärd, Mattias Svensson, Ing-Marie Jonsson |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
STAT3 Transcription Factor 0301 basic medicine T cell Arthritis Inflammation Systemic inflammation Receptor IGF Type 1 Arthritis Rheumatoid Mice 03 medical and health sciences 0302 clinical medicine Insulin receptor substrate medicine Animals Humans Interleukin 6 Molecular Biology Mice Inbred BALB C biology Interleukin-6 business.industry Synovial Membrane FOXP3 Middle Aged medicine.disease 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Rheumatoid arthritis Immunology biology.protein Th17 Cells Molecular Medicine medicine.symptom business Signal Transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1863:2158-2170 |
| ISSN: | 0925-4439 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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