Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor

Abstract

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.

Fig. 1

Inflammatory pathways activated by IL-6. At joint level, IL-6 induces pannus formation, osteoclast activation and mediates chronic synovitis.

Fig. 2

IL-6 signalling mechanism. IL-6-mediated signal transduction through classical (A) and trans-signalling (B) pathways. In IL-6 trans-signalling, sIL-6R is generated either by limited proteolysis of the membrane-bound IL-6R or by alternative mRNA splicing. In both classical and trans-signalling, responses are elicited through engagement with membrane-bound gp130.

Fig. 3

The systemic effects of IL-6. Systemically, IL-6 actions include stimulation of acute-phase proteins and hepatocyte proliferation in the liver, induction of anaemia and effects on lipids and lipid metabolism, impairment of HPA axis and osteoporosis.

Fig. 4

Potential sites for intervention in RA. Based on the present knowledge of RA pathogenesis, therapeutic strategies can influence the outcome of initial or late-phase processes. IL-6 inhibition can influence the initial autoimmune reaction between antigen-presenting cells and T and B cells or the later stage in tissue destruction when synovial cells, chondrocytes and bone-derived cells are involved.