Soluble vascular cell adhesion molecule 1 mediation of monocyte chemotaxis in rheumatoid arthritis

• Published in: Arthritis and rheumatism 2000-05, Vol.43 (5), p.1122-1133
• Main Authors: Tokuhira, Michihide, Hosaka, Shigeru, Volin, Michael V., Haines, G. Kenneth, Katschke, Kenneth J., Kim, Soyun, Koch, Alisa E.
• Format: Article
• Language: English
• Subjects: Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Arthritis, Rheumatoid - physiopathology; Chemotaxis, Leukocyte - drug effects; Humans; Integrin alpha4beta1; Integrins - biosynthesis; Integrins - physiology; Macrophages - metabolism; Monocytes - cytology; Monocytes - metabolism; Receptors, Lymphocyte Homing - biosynthesis; Receptors, Lymphocyte Homing - physiology; Signal Transduction - physiology; Solubility; Synovial Fluid - cytology; Up-Regulation; Vascular Cell Adhesion Molecule-1 - pharmacology; Vascular Cell Adhesion Molecule-1 - physiology
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/1529-0131(200005)43:5<1122::AID-ANR23>3.0.CO;2-7

Objective Rheumatoid arthritis (RA) is characterized by infiltration of leukocytes, including monocyte/macrophages, into synovial tissue (ST), but factors mediating the ingress of these cells are poorly understood. Vascular cell adhesion molecule 1 (VCAM‐1) plays an important role in adhesion of leukocytes to the vasculature. This study was undertaken to test the hypothesis that soluble VCAM‐1 (sVCAM‐1) might mediate chemotaxis of monocytes in RA. Methods Chemotaxis assays were performed using a modified Boyden chamber to determine the effects of sVCAM‐1 on and the role of very late activation antigen 4 (VLA‐4) in peripheral blood (PB) monocyte migration. Synovial fluids (SF) were immunodepleted of sVCAM‐1 to identify a role for sVCAM‐1 in RA. Immunohistochemistry and flow cytometry analyses were performed to show the expression of VLA‐4 in ST, SF, and PB. Tyrosine phosphorylation was studied by Western blot analysis on PB monocyte lysates in the presence of signaling inhibitors. Results Soluble VCAM‐1 induced monocyte migration in the nM range, in a concentration‐dependent manner. Anti–VLA‐4 significantly inhibited sVCAM‐1–induced monocyte migration, suggesting that sVCAM‐1 acts in part via a VLA‐4–dependent mechanism. In RA SF, incubation with anti–VCAM‐1 resulted in a reduction in the ability to induce monocyte migration (mean 28%). VLA‐4 immunolocalized to RA ST, SF, or PB, monocytes, macrophages, and lymphocytes. Soluble VCAM‐1 stimulated tyrosine phosphorylation in monocytes, and pertussis toxin, chelerythrine chloride, and staurosporine significantly reduced sVCAM‐1–mediated monocyte chemotaxis, suggesting that signaling pathways via G proteins and protein kinase C are required for sVCAM‐1–mediated monocyte migration. Conclusion These results demonstrate a novel function for sVCAM‐1 as a monocyte chemotactic agent in RA and suggest a new potential target for modulating monocyte ingress into inflamed RA ST.