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