Interleukin-6: a new therapeutic target in systemic sclerosis?

Abstract

Interleukin-6 (IL-6) is a classic pro-inflammatory cytokine critical in mounting an effective immune response. It is secreted by a wide array of cell types; however, its effector cells are more restricted, owing to the fact that very few cells, except lymphocytes and hepatocytes, express the functional membrane IL-6 receptor thus reducing the number of IL-6-responsive cells. Trans-signalling, the shedding of the membrane-bound form of the IL-6 receptor into the local microenvironment, greatly increases the range of cells that can respond. IL-6 has been demonstrated to have a pivotal role in the pathogenesis of rheumatoid arthritis, Castleman's disease and Crohn's disease exemplified by the use of an anti-IL-6 biological therapy. However, IL-6 is also associated with the autoimmune disease systemic sclerosis (SSc) and has been shown to be directly fibrotic. Elevated levels of IL-6 are found in SSc patients and this correlates with skin thickness, suggesting a causal effect. This review focuses on the role of IL-6 in SSc, a chronic autoimmune disease with fibrosis. In particular, we will examine the evidence base of the role of IL-6 in fibrosis in this condition, especially the downstream effector pathways. We will then argue why molecular targeting of IL-6 is a promising therapeutic target in this fibrosing disease.

Keywords: Th17; fibrosis; interleukin-6; interleukin-6 signalling; systemic sclerosis.

Figure 1

IL-6 signalling and trans-signalling. Hepatocytes and leukocytes including T and B cells express the IL-6R (a) and signal through what is termed classic signalling as the cytokine IL-6 binds both the IL-6R and the common shared subunit gp130, which leads to JAK activation and STAT3 phosphorylation and/or RAS/MAPK activation and to transcription of target genes. The red indicates transcription factors. (b) Demonstration of trans-signalling in all cells that do not express the IL-6R, but respond by the binding of soluble IL-6R to IL-6 and gp130 and downstream signalling. IL-6R can be shed from the cell membrane via the enzyme ADAM17/TACE (yellow box) or through an alternative spliced IL-6R gene or to a lesser degree ADAM10 can release IL-6R. Activation of T cells leads to shedding of IL-6R from the membrane, which can then bind IL-6 and initiates downstream signalling in the target cell. TACE, tumour necrosis factor-α-converting enzyme.