Abstract
Junctional adhesion molecule-C (JAM-C) is an adhesion molecule involved in transendothelial migration of leukocytes. In this study, we examined JAM-C expression in the synovium and investigated the role of this molecule in two experimental mouse models of arthritis. JAM-C expression was investigated by reverse transcriptase-polymerase chain reaction and immunohistochemistry. The effects of a monoclonal anti-JAM-C antibody were assessed in antigen-induced arthritis (AIA) and K/BxN serum transfer-induced arthritis. JAM-C was expressed by synovial fibroblasts in the lining layer and associated with vessels in the sublining layer in human and mouse arthritic synovial tissue. In human tissue, JAM-C expression was increased in rheumatoid arthritis (RA) as compared to osteoarthritis synovial samples (12.7 ± 1.3 arbitrary units in RA versus 3.3 ± 1.1 in OA; p < 0.05). Treatment of mice with a monoclonal anti-JAM-C antibody decreased the severity of AIA. Neutrophil infiltration into inflamed joints was selectively reduced as compared to T-lymphocyte and macrophage infiltration (0.8 ± 0.3 arbitrary units in anti-JAM-C-treated versus 2.3 ± 0.6 in isotype-matched control antibody-treated mice; p < 0.05). Circulating levels of the acute-phase protein serum amyloid A as well as antigen-specific and concanavalin A-induced spleen T-cell responses were significantly decreased in anti-JAM-C antibody-treated mice. In the serum transfer-induced arthritis model, treatment with the anti-JAM-C antibody delayed the onset of arthritis. JAM-C is highly expressed by synovial fibroblasts in RA. Treatment of mice with an anti-JAM-C antibody significantly reduced the severity of AIA and delayed the onset of serum transfer-induced arthritis, suggesting a role for JAM-C in the pathogenesis of arthritis.
Highlights
The recruitment of leukocytes to inflamed tissues is a highly regulated multistep process, which includes leukocyte rolling on the vascular endothelium, activation of leukocytes and subsequent firm adhesion to endothelial ligands, transendothelial migration from the vascular lumen into the surrounding tissue, and migration of inflammatory cells through the tissue in response to chemokine gradients [1,2]
Junctional adhesion molecule-C (JAM-C) is highly expressed by synovial fibroblasts in rheumatoid arthritis (RA)
Treatment of mice with an anti-junctional adhesion molecules (JAMs)-C antibody significantly reduced the severity of antigen-induced arthritis (AIA) and delayed the onset of serum transfer-induced arthritis, suggesting a role for JAM-C in the pathogenesis of arthritis
Summary
The recruitment of leukocytes to inflamed tissues is a highly regulated multistep process, which includes leukocyte rolling on the vascular endothelium, activation of leukocytes and subsequent firm adhesion to endothelial ligands, transendothelial migration from the vascular lumen into the surrounding tissue, and migration of inflammatory cells through the tissue in response to chemokine gradients [1,2]. The successive events in this cascade are mediated by coordinated interaction of adhesion molecules expressed by leukocytes, endothelial cells, and the surrounding tissues. = intraperitoneal; JAM = junctional adhesion molecule; LFA-1 = lymphocyte function-associated antigen-1; mBSA = methylated bovine serum albumin; OA = osteoarthritis; PBS = phosphate-buffered saline; PCR = polymerase chain reaction; PECAM-1 = platelet endothelial cell adhesion molecule-1; RA = rheumatoid arthritis; RT = reverse transcriptase; SAA = serum amyloid A; Tc = technetium; VEGF = vascular endothelial growth factor. JAM-C is expressed in mesenchymal and epithelial cells, suggesting that in addition to its role in inflammatory cell recruitment, it might contribute to the retention of leukocytes within inflamed tissues [9,10]
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