Activation of the Interferon-gamma Signaling Pathway in Systemic Lupus Erythematosus Peripheral Blood Mononuclear Cells

作者：Karonitsch Thomas^*; Feierl Eva; Steiner Carl Walter; Dalwigk Karolina; Korb Adelheid; Binder Nikolaus; Rapp Alfred; Steiner Guenter; Scheinecker Clemens; Smolen Josef; Aringer Martin

来源：Arthritis and Rheumatism, 2009, 60(5): 1463-1471.

DOI：10.1002/art.24449

Objective. To investigate interferon-gamma (IFN gamma) signaling in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) by analyzing IFN gamma receptor (IFN gamma R) expression, STAT-1 expression and phosphorylation, and the regulation of IFN gamma-inducible genes.
Methods. Fluorocytometry was used to investigate expression of STAT-1, pSTAT-1, CD95, HLA-DR, class I major histocompatibility complex (MHC), IFN gamma-inducible 10-kd protein (IP-10), monokine induced by IFN gamma (Mig), and IFN gamma R in PBMCs from SLE patients and healthy individuals. STAT-I phosphorylation was determined by fluorocytometry and Western blotting after stimulation with IFN alpha or IFN gamma. Quantitative polymerase chain reaction was used to assess messenger RNA (mRNA) expression of the IFN gamma-inducible genes IP-10 and Mig shortly after preparation or after stimulation with IFN gamma in monocytes.
Results. STAT-1 expression was increased in PBMCs from SLE patients and correlated significantly with disease activity and with the IFN gamma-inducible expression of CD95 and HLA-DR. STAT-I expression also showed a trend toward association with class I MHC expression. In addition, the expression of other IFN gamma-inducible genes, such as IP-10 or Mig, was increased in SLE monocytes. While STAT-1 phosphorylation in SLE PBMCs and PBMCs from healthy individuals was similar after IFN alpha stimulation, incubation with IFN-gamma induced STAT-1 phosphorylation only in SLE lymphocytes. Moreover, SLE monocytes showed a considerably higher increase in pSTAT-1 expression upon IFN gamma stimulation than monocytes from healthy individuals. Increased responsiveness of SLE monocytes to IFN gamma was also confirmed on the mRNA level, where expression of the IFN-inducible, STAT-1-dependent genes IP-10 and Mig was more efficiently increased in SLE cells. However, IFN gamma R was similarly expressed on SLE lymphocytes and monocytes and those from healthy individuals.
Conclusion. In addition to supporting the role of IFNs in SLE immunopathogenesis in general, the findings of the present study support a role of IFN gamma in this disease.

• 出版日期2009-5