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Proinflammatory Role of Fractalkine (CX3CL1) in Rheumatoid Arthritis
SABINE BLASCHKE, MICHAEL KOZIOLEK, ANDREAS SCHWARZ, PETER BENÖHR, PETER MIDDEL, GERHARD SCHWARZ, KLAUS-M. HUMMEL, GERHARD A. MÜLLER
ABSTRACT.
Objective. Fractalkine (CX3CL1) represents the sole member of the so-called CX3C chemokines. In rheumatoid arthritis (RA), functional studies suggest a role for this chemokine in monocyte chemotaxis and angiogenesis in the rheumatoid synovium. We analyzed the expression of fractalkine within different T cell subsets of the peripheral blood and expression of its receptor CX3CR1 within the rheumatoid synovium to further characterize its pathogenic role in RA. Methods. Peripheral blood mononuclear cells (PBMC) were isolated from 17 patients with RA and analyzed by flow cytometry in comparison to healthy blood donors. To identify the T helper cell cytokine profile of fractalkine-expressing cells, flow cytometric analysis of PBMC was performed after stimulation with PMA and ionomycin. Expression of fractalkine and its receptor was characterized in RA synovium by immunohistochemistry and laser capture microdissection microscopy. Results. Flow cytometric analysis of fractalkine-expressing T cell subsets revealed a low proportion of fractalkine-expressing CD4+ and CD8+ T cells in both RA patients and controls. In addition, fractalkine was predominantly expressed in CD4+ T cells with a Th1-type cytokine expression profile. In RA synovium, fractalkine was detected in synovial macrophages, dendritic cells, endothelial cells, and a small proportion of T cells. The fractalkine receptor CX3CR1 was found in synovial macrophages, dendritic cells, and T cells as well as in synovial fibroblasts. Fractalkine stimulation of cultured synovial fibroblasts resulted in a marked upregulation of matrix metalloproteinase-2 (MMP-2) production. Conclusion. The results suggest that fractalkine may represent a Th1-type chemokine. Upregulation of MMP-2 production in synovial fibroblasts upon fractalkine stimulation in vitro supports the hypothesis of a proinflammatory role of this chemokine in RA. (J Rheumatol 2003;30:1918-27) Key Indexing Terms:
CHEMOKINES
From the Department of Nephrology and Rheumatology, Department of Pathology, and Department of Orthopaedics, University of Goettingen, Goettingen; and the Department of Rheumatology, Medical Clinic III, University of Dresden, Dresden, Germany. Supported by a grant of the Forschungsförderungsprogramm 2001 of the University of Goettingen. S. Blaschke, MD; M. Koziolek, MD; A. Schwarz, Medical Student; P. Benöhr, MD; G.A. Müller, Professor of Medicine, Head, Department of Nephrology and Rheumatology; P. Middel, MD, Department of Pathology; G. Schwarz, MD, Department of Orthopaedics, University of Goettingen; K.M. Hummel, MD, Medical Clinic III, Department of Rheumatology, University of Dresden. Address reprint requests to Dr. S. Blaschke, Department of Nephrology and Rheumatology, Georg-August-University, Robert-Koch Strasse 40, 37075 Göttingen, Germany. E-mail sblasch@gwdg.de Submitted July 24, 2002; revision accepted February 13, 2003. |