Proinflammatory role of fractalkine (CX3CL1) in rheumatoid arthritis.
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.


CONCLUSIONS
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.
Blaschke
Sabine
S
Department of Nephrology and Rheumatology, Georg-August-University of Goettingen, Robert-Koch Strasse 40, 37075 Goettingen, Germany. sblach@gwdg.de
Koziolek
Michael
M
Schwarz
Andreas
A
Benöhr
Peter
P
Middel
Peter
P
Schwarz
Gerhard
G
Hummel
Klaus-M
KM
Müller
Gerhard A
GA
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis; D001483:Base Sequence; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000032:analysis*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis*; D008875:Middle Aged; D008969:Molecular Sequence Data; D011379:Prognosis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D013582:Synovial Fluid / Q000737:chemistry; D015854:Up-Regulation
D015415:Biomarkers; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D018836:Inflammation Mediators; D008565:Membrane Proteins; D020778:Matrix Metalloproteinase 2