title: The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Pia
authors.initials: P
authors.lastname: Isomäki
authors.affiliation: 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.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Junttila
authors.affiliation: 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.
authors.forename: Krista-Liisa
authors.initials: KL
authors.lastname: Vidqvist
authors.affiliation: 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.
authors.forename: Markku
authors.initials: M
authors.lastname: Korpela
authors.affiliation: 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.
authors.forename: Olli
authors.initials: O
authors.lastname: Silvennoinen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D007371:Interferon-gamma; D053612:Janus Kinases
keywords: IL-6; cytokine; rheumatoid arthritis; signal transduction