Journal
RHEUMATOLOGY
Volume 49, Issue 1, Pages 15-24Publisher
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/kep329
Keywords
Interleukin-6; Rheumatoid arthritis; Trans-signalling; Joint destruction; Systemic effects; Immune response; Receptor inhibition
Categories
Funding
- F. Hoffmann-La Roche Ltd.
- Roche
- Allergan
- Boehringer Ingelheim
- Chelsea Therapeutics
- Eli Lilly
- GSK
- Jazz Pharmaceuticals
- Merrimack Pharmaceutical
- MSD
- Pfizer
- Pierre Fabre Medicament
- Schering-Plough
- UCB Celltech
- Wyeth for advisory boards
- consultancy and speaker bureaus
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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.
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