Pia Isomäki1, Ilkka Junttila2, Krista-Liisa Vidqvist3, Markku Korpela3, Olli Silvennoinen2. 1. School of Medicine, University of Tampere, Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Fimlab Laboratories and Department of Internal Medicine, Tampere University Hospital, Tampere, Finland School of Medicine, University of Tampere, Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Fimlab Laboratories and Department of Internal Medicine, Tampere University Hospital, Tampere, Finland pia.isomaki@uta.fi. 2. School of Medicine, University of Tampere, Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Fimlab Laboratories and Department of Internal Medicine, Tampere University Hospital, Tampere, Finland School of Medicine, University of Tampere, Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Fimlab Laboratories and Department of Internal Medicine, Tampere University Hospital, Tampere, Finland. 3. School of Medicine, University of Tampere, Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, Fimlab Laboratories and Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
Abstract
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-γ, 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.
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 RApatients and healthy volunteers by RT-PCR. Basal and cytokine (IFN-γ, 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 RApatients. 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 RApatients. 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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