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THU0543 Constitutive Activation of STAT3 in Rheumatoid Arthritis Correlates with IL-6 Levels
  1. P. Isomäki1,
  2. I. Junttila2,
  3. K.-L. Vidqvist1,
  4. M. Korpela1,
  5. O. Silvennoinen2
  1. 1Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital
  2. 2School of Medicine, University of Tampere, Tampere, Finland

Abstract

Background Many cytokines involved in the inflammatory process in rheumatoid arthritis (RA) activate the JAK-STAT pathways. Therapeutic drugs that inhibit these pathways are currently being developed for RA.

Objectives To investigate whether there are disease-related alterations in the activity of JAK-STAT pathways in RA, we have studied the expression and activation of STAT1 and STAT3 in unstimulated cells, and in response to interferon (IFN)-γ, interleukin (IL)-6 and IL-10 stimulation.

Methods The expression of STAT1 and STAT3 mRNA in peripheral blood (PB) and synovial fluid (SF) T cells and monocytes were studied from patients with RA and healthy volunteers by reverse transcriptase polymerase chain reaction. Basal and cytokine-induced STAT phosphorylations were analysed in PB T cells and monocytes using multicolour flow cytometric analysis. Cytokine levels were determined by ELISA.

Results STAT3 mRNA levels were upregulated 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 degree of STAT3 phosphorylation in CD4+ T cells and monocytes. The IL-6-mediated STAT3 activation was downregulated 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.

Conclusions These 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.

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.3075

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