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

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.