Interleukin-18: A Mediator of Inflammation and Angiogenesis in Rheumatoid Arthritis

Interleukin-18 (IL-18) is a highly regulated inflammatory cytokine that is elevated in synovial tissues and synovial fluids of patients with rheumatoid arthritis (RA) compared with patients with osteoarthritis (OA) and patients with other arthropathies. Within the RA joint, IL-18 can contribute to the inflammatory process by inducing leukocyte extravasation through upregulation of endothelial cell adhesion molecules, the release of chemokines from RA synovial fibroblasts, and directly as a monocytes, lymphocyte, and neutrophil chemoattractant. IL-18 can also help maintain and develop the inflammatory pannus by inducing endothelial cell migration and angiogenesis. IL-18 does this directly by binding and activating endothelial cells and indirectly by inducing RA synovial fibroblasts to produce angiogenic chemokines and vascular endothelial growth factor. IL-18 is present in RA synovial fluid in high levels, where it functions as an angiogenic mediator and leukocyte chemoattractant. IL-18 mediates all these inflammatory processes by binding to its receptor, IL-18 receptor, and initiating the activation of different signaling cascades leading to changes in target cells gene expression and behavior. IL-18 has been identified as a potential therapeutic target in the treatment of RA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90485/1/jir-2E2011-2E0050.pd

A cell-cycle independent role for p21 in regulating synovial fibroblast migration in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and destruction of cartilage and bone. The fibroblast-like synoviocyte (FLS) population is central to the development of pannus by migrating into cartilage and bone. We demonstrated previously that expression of the cell cycle inhibitor p21 is significantly reduced in RA synovial lining, particularly in the FLS. The aim of this study was to determine whether reduced expression of p21 in FLS could alter the migratory behavior of these cells. FLS were isolated from mice deficient in p21 (p21((-/-))) and were examined with respect to growth and migration. p21((-/-) )and wild-type (WT) FLS were compared with respect to migration towards chemoattractants found in RA synovial fluid in the presence and absence of cell cycle inhibitors. Restoration of p21 expression was accomplished using adenoviral infection. As anticipated from the loss of a cell cycle inhibitor, p21((-/-) )FLS grow more rapidly than WT FLS. In examining migration towards biologically relevant RA synovial fluid, p21((-/-) )FLS display a marked increase (3.1-fold; p < 0.05) in migration compared to WT cells. Moreover, this effect is independent of the cell cycle since chemical inhibitors that block the cell cycle have no effect on migration. In contrast, p21 is required to repress migration as restoration of p21 expression in p21((-/-) )FLS reverses this effect. Taken together, these data suggest that p21 plays a novel role in normal FLS, namely to repress migration. Loss of p21 expression that occurs in RA FLS may contribute to excessive invasion and subsequent joint destruction