Journal
RHEUMATOLOGY
Volume 54, Issue 6, Pages 1103-1113Publisher
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/keu430
Keywords
rheumatoid arthritis; cytokine; IL-6; signal transduction
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Funding
- Medical Research Fund of Tampere University Hospital [9M120, 9P050]
- Sigrid Juselius Foundation
- Tampere Tuberculosis Foundation
- Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital [X51409]
- Medical Research Council of Academy of Finland
- Finnish Cancer Foundation
- Maire Lisko Foundation
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Objective. Many cytokines involved in RA activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Therapeutic drugs that inhibit these pathways are being developed for RA. To investigate disease-related alterations in the activity of JAK-STAT pathways in RA, we studied the expression and activation of STAT1 and STAT3 in unstimulated and cytokine-stimulated cells and determined the levels of circulating cytokines. Methods. The expression of STAT1 and STAT3 mRNA in peripheral blood (PB) and SF T cells and monocytes was studied in RA patients and healthy volunteers by RT-PCR. Basal and cytokine (IFN-gamma, IL-6, IL-10)-induced STAT phosphorylation was analysed in PB T cells and monocytes using multicolour flow cytometric analysis. Results. STAT3 mRNA levels were up-regulated in both PB and SF T cells and monocytes from RA patients. STAT1 expression was elevated in SF monocytes. The levels of phospho-STAT3 in resting PB T cells and monocytes were significantly higher in patients with RA than in healthy volunteers. IL-6 levels were elevated in RA plasma and correlated with the level of STAT3 phosphorylation in CD4(+) T cells and monocytes. IL-6-mediated STAT3 activation was deregulated in T cells from RA patients. IL-6-induced phosphorylation of STAT3 was decreased in CD4(+) T cells from patients with high plasma IL-6 levels and constitutive STAT3 phosphorylation. Conclusion. The results suggest that IL-6 induces hyperactivation of STAT3 in circulating immune cells in active RA, and this subsequently desensitizes the IL-6 response in T cells.
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