Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor.
RA is a chronic, debilitating disease in which articular inflammation and joint destruction are accompanied by systemic manifestations including anaemia, fatigue and osteoporosis. IL-6 is expressed abundantly in the SF of RA patients and is thought to mediate many of the local and systemic effects of this disease. Unlike a number of other cytokines, IL-6 can activate cells through both membrane-bound (IL-6R) and soluble receptors (sIL-6R), thus widening the number of cell types responsive to this cytokine. Indeed, trans-signalling, where IL-6 binds to the sIL-6R, homodimerizes with glycoprotein 130 subunits and induces signal transduction, has been found to play a key role in acute and chronic inflammation. Elevated levels of IL-6 and sIL-6R in the SF of RA patients can increase the risk of joint destruction and, at the joint level, IL-6/sIL-6R can stimulate pannus development through increased VEGF expression and increase bone resorption as a result of osteoclastogenesis. Systemic effects of IL-6, albeit through conventional or trans-signalling, include regulation of acute-phase protein synthesis, as well as hepcidin production and stimulation of the hypothalamo-pituitary-adrenal axis, the latter two actions potentially leading to anaemia and fatigue, respectively. This review aims to provide an insight into the biological effects of IL-6 in RA, examining how IL-6 can induce the articular and systemic effects of this disease.
Dayer
Jean-Michel
JM
Faculty of Medicine, Centre Médical Universitaire, Geneva, Switzerland.
Choy
Ernest
E
D000208:Acute Disease; D056704:Adaptive Immunity; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology; D001862:Bone Resorption / Q000276:immunology; D002908:Chronic Disease; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
D015850:Interleukin-6; D019947:Receptors, Interleukin-6