Increased monocyte transcription of the proteinase 3 gene in small vessel vasculitis

Department of Nephrology, Lund University, Lund, Sweden.
Clinical & Experimental Immunology (Impact Factor: 3.04). 08/2005; 141(1):174-82. DOI: 10.1111/j.1365-2249.2005.02819.x
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Proteinase 3 (PR3) is a pleiotropic and destructive serine protease and it is also a major target for autoantibodies in systemic small vessel vasculitis. We have shown recently that patients in stable remission have increased circulating levels of PR3, independent of autoantibody titre, inflammation, neutrophil degranulation and renal function. Here we explore the possibility of increased PR3 gene transcription. RNA was purified from peripheral blood monocytes from vasculitis patients and controls. Specific mRNA was measured by TaqMan real-time polymerase chain reaction (PCR). The monocyte-like cell lines THP-1 and U937 and human peripheral blod monocytes from healthy controls were stimulated with cytokines and lipopolysaccharide (LPS) for different time periods. PR3 protein was measured in plasma with enzyme-linked immunosorbent assay (ELISA). The median result for PR3 mRNA was 9.6 (1.8-680) for 22 patients, compared to 1 (0.1-2.8) for the 15 healthy controls. Elastase expression was also significantly increased, whereas myeloperoxidase and interleukin-8 were not. Stimulation of monocytes with tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma or LPS did not result in any increase of PR3 or elastase transcription, whereas interleukin (IL)-8 transcription was increased 10-fold. Circulating monocytes from patients with systemic vasculitis display increased PR3 gene transcription compared to healthy controls and patients with sytemic lupus erythematosus (SLE). This may be important for the development of vasculitis. Our results do not favour a role for cytokines, antineutrophil cytoplasmic antibodies (ANCA) or immunosuppressive medication in the upregulation of PR3 transcription in vasculitis.

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    • "ANCA binding to target antigens with subsequent activation of neutrophils resulting in premature degranulation and endothelial cell damage (ANCA-cytokine sequence theory) has been (and still is) controversially discussed as key event in the pathogenesis of GPA [17]. Recently, myelomonocytic cells have been shown to increase PR3 gene transcription in small vessel vasculitis as well [4]. In addition, high anti-PR3 concentration in patients with acute vasculitis has been shown to correlate with an activated adhesion molecule phenotype in circulating monocytes [18]. "
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