Interferon signals and monocytic sensitization of the interferon-γ signaling pathway in the peripheral blood of patients with rheumatoid arthritis.

Both type I interferons (IFNα and IFNβ) and type II IFN (IFNγ) signal via pSTAT-1. Immunohistochemistry and the gene expression signatures of rheumatoid arthritis (RA) synovial tissue suggest an activated IFN/STAT-1 signaling pathway. The aim of this study was to determine the systemic activity of the IFN/STAT-1 signaling pathway in the peripheral blood cells of patients with RA. Fluorocytometry or quantitative polymerase chain reaction was used to measure the expression of STAT-1, pSTAT-1, and IFN-inducible genes (monokine induced by interferon-γ [MIG], interferon-γ-inducible protein 10 [IP-10], and 2',5'-oligoadenylate synthetase [OAS]) in the peripheral blood mononuclear cells (PBMCs) and purified CD14+ peripheral blood monocytes of patients with RA and healthy control subjects. PBMCs were also incubated for 48 hours with IFNs and several other cytokines to investigate influences on STAT-1 levels. To examine the significance of STAT-1 activation in RA monocytes after stimulation with IFNγ, the expression of pSTAT-1 and of the IFNγ-inducible chemokine MIG was measured using fluorocytometry. Levels of STAT-1 were significantly increased in peripheral lymphocytes and monocytes from patients with RA compared with those from healthy control subjects. STAT-1 levels correlated well with RA disease activity, as measured by the Disease Activity Score in 28 joints and the Clinical Disease Activity Index. Furthermore, STAT-1 messenger RNA expression in RA CD14+ monocytes correlated with the expression of other IFN-target genes, such as IP-10, OAS, or MIG. In RA PBMCs, STAT-1 expression was increased not only by IFNs but also by tumor necrosis factor. RA monocytes demonstrated a considerably higher increase in pSTAT-1 and MIG levels upon IFNγ stimulation when compared with monocytes from control subjects, indicating that RA monocytes are more sensitive to IFNγ stimulation. In addition to supporting the role of IFNs in systemic proinflammatory activity, the results of this study further suggest preactivation of the IFNγ/STAT-1 signaling pathway, especially in RA monocytes.

Karonitsch T ，von Dalwigk K ，Steiner CW ，Blüml S ，Steiner G ，Kiener HP ，Smolen JS ，Aringer M ... -  《-》

Activation of the interferon-gamma signaling pathway in systemic lupus erythematosus peripheral blood mononuclear cells.

Karonitsch T ，Feierl E ，Steiner CW ，Dalwigk K ，Korb A ，Binder N ，Rapp A ，Steiner G ，Scheinecker C ，Smolen J ，Aringer M ... -  《ARTHRITIS AND RHEUMATISM》

The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels.

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. 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. 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. 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.

Isomäki P ，Junttila I ，Vidqvist KL ，Korpela M ，Silvennoinen O ... -  《-》

Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma.

Radstake TR ，Roelofs MF ，Jenniskens YM ，Oppers-Walgreen B ，van Riel PL ，Barrera P ，Joosten LA ，van den Berg WB ... -  《ARTHRITIS AND RHEUMATISM》

Increased expression of Siglec-1 on peripheral blood monocytes and its role in mononuclear cell reactivity to autoantigen in rheumatoid arthritis.

Xiong YS ，Cheng Y ，Lin QS ，Wu AL ，Yu J ，Li C ，Sun Y ，Zhong RQ ，Wu LJ ... -  《-》