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Ann Rheum Dis. Mar 2004; 63(3): 233–239.
PMCID: PMC1754903

Activation of the STAT1 pathway in rheumatoid arthritis

Abstract

Background: Expression of signal transducer and activator of transcription 1 (STAT1), the mediator of interferon (IFN) signalling, is raised in synovial tissue (ST) from patients with rheumatoid arthritis (RA).

Objectives: To determine the extent to which this pathway is activated by phosphorylation in RA synovium. Additionally, to investigate the cellular basis of STAT1 activation in RA ST.

Methods: ST specimens from 12 patients with RA and 14 disease controls (patients with osteoarthritis and reactive arthritis) were analysed by immunohistochemistry, using antibodies to STAT1, tyrosine phosphorylated STAT1, and serine phosphorylated STAT1. Lysates of cultured fibroblast-like synoviocytes stimulated with IFNß were analysed by western blotting. Phenotypic characterisation of cells expressing STAT1 in RA ST was performed by double immunolabelling for STAT1 and CD3, CD22, CD55, or CD68.

Results: Raised levels of total STAT1 protein and both its activated tyrosine and serine phosphorylated forms were seen in RA synovium as compared with controls. STAT1 was predominantly abundant in T and B lymphocytes in focal inflammatory infiltrates and in fibroblast-like synoviocytes in the intimal lining layer. Raised levels of STAT1 are sustained in cultured RA compared with OA fibroblast-like synoviocytes, and STAT1 serine and tyrosine phosphorylation is rapidly induced upon stimulation with IFNß.

Conclusion: These results demonstrate activation of the STAT1 pathway in RA synovium by raised STAT1 protein expression and concomitantly increased tyrosine (701) and serine (727) phosphorylation. High expression of STAT1 is intrinsic to RA fibroblast-like synoviocytes in the intimal lining layer, whereas activation of the pathway by phosphorylation is an active process.

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Selected References

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Figures and Tables

Figure 1
Increased STAT1 phosphorylation on tyrosine and serine in RA ST as compared with controls. Serial ST sections from 12 patients with RA and 14 controls were stained for STAT1-phospho-tyrosine and STAT1-phospho-serine using aminoethylcarbazole as dye (A) ...
Figure 2
Immunohistochemical double labelling of the ST of four patients with RA (table 1; patients Nos 4, 5, 7, and 13; representative sections are shown) for STAT1 and CD22+ B cells (A), CD3+ T cells (B), CD55+ fibroblast-like synoviocytes (C), or CD68+ macrophages ...
Figure 3
Double immunofluorescence was performed on the ST of four patients with RA (table 1; patients Nos 1, 2, 3, and 10). (A) STAT1 (tetramethylrhodamine) and CD22+ B cells, CD3+ T cells, CD55+ fibroblast-like synoviocytes, or CD68+ macrophages (fluorescein). ...
Figure 4
STAT1 expression is raised in RA compared with OA fibroblast-like synoviocytes (top panel) and STAT1 tyrosine and serine phosphorylation are induced by stimulation with IFNß (second and third panels). Fourth passage RA and OA synoviocytes were ...

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