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.