Interleukin-6--a key mediator of systemic and local symptoms in rheumatoid arthritis.
Interleukin-6 (IL-6) is a pleiotropic cytokine, present at elevated levels in patients with rheumatoid arthritis (RA). Il-6 signaling involves both a specific IL-6 receptor (IL-6R) and a ubiquitous signal-transducing protein, gp130 that is also utilized by other members of the IL-6 family. Il-6 signaling occurs by two mechanisms. Conventional signaling involves the binding of IL-6 to transmembrane IL-6R on cells expressing this receptor. In contrast, trans-signaling involves binding between the complex of soluble IL-6R/IL-6 and membrane-bound gp130. Trans-signaling allows IL-6 to affect cells that do not express IL-6R, including many synovial cells. The biological activities of IL-6 contribute to both systemic and local RA symptoms. Il-6 is a strong inducer of the acute-phase response, which can result in fever, secondary amyloidosis, anemia, and elevations in acute-phase proteins, such as C-reactive protein (CRP). The ability of IL-6 to induce B-cell differentiation may lead to the formation of rheumatoid factor and other autoantibodies. In joints, IL-6 promotes osteoclast activation and induces the release of matrix metalloproteinases, thus contributing to joint damage. In patients with RA, IL-6 levels correlate with markers of disease activity and clinical symptoms, and animal studies support the concept that this cytokine plays a role in the development of inflammatory arthritis. Clinical trials with tocilizumab, a humanized monoclonal antibody to soluble IL-6R, have shown that blocking IL-6 signaling reduces RA symptoms and markers of disease activity. Current evidence thus strongly supports the association between IL-6 and RA symptoms and suggests that IL-6 blockade will be a useful therapeutic strategy for patients with this disease.
Cronstein
Bruce N
BN
NYU School of Medicine, New York University Medical Center, New York, New York 10016, USA. cronsb01@med.nyu.edu
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology*; D050822:Cytokine Receptor gp130 / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130; C502936:tocilizumab