Interleukin-6 is currently attracting significant interest as a potential therapeutic target in systemic sclerosis (SSc). In this paper, the biology of interleukin-6 is reviewed, and the evidence for interleukin-6 dysregulation in SSc is explored. The role of inteleukin-6 classical and trans signalling pathways in SSc relevant phenomena such as chronic inflammation, autoimmunity, endothelial cell dysfunction, and fibrogenesis is discussed. The existing evidence that interventions designed to block interleukin-6 signalling are of therapeutic relevance in SSc is evaluated. 1. Introduction Systemic sclerosis (SSc) is a connective tissue disease characterised by fibrosis, vasculopathy, and immunological abnormalities. Over recent years, it has become clear that inflammation plays a crucial role in mediating the pathophysiological process underlying SSc, especially early in the disease. Endothelial cell activation and dysfunction are central to the disease pathogenesis, may be driven by a proinflammatory environment, and may result in the generation of a profibrotic phenotype. Interleukin-6 (IL-6) is a pleiotropic cytokine. In addition to its role in the acute phase response, IL-6 has diverse roles in driving chronic inflammation, autoimmunity, endothelial cell dysfunction, and fibrogenesis. Therefore, it is currently attracting a great deal of interest in the rheumatology community as a potential therapeutic agent in SSc, a disease which at present lacks treatments directed at the underlying pathogenesis. Recent evidence has suggested that IL-6 may play important roles in endothelial cell dysfunction and fibrogenesis in this disease, and clinical trials are currently being designed to further explore whether Tocilizumab, a monoclonal antibody directed against the IL-6 receptor, may be of therapeutic benefit to patients with SSc. 2. Interleukin-6 Biology Interleukin-6 biology is complex. Few cells express the interleukin-6 receptor (IL-6R, gp80). This receptor is expressed on hepatocytes, monocytes, B cells, and neutrophils in humans. It is also found on a subset of T cells, but there is evidence that T cells respond to IL-6 predominantly through a process known as trans signalling [1]. Endothelial cells and fibroblasts do not express the IL-6R and are also thought to respond to IL-6 through trans signalling [2]. sIL-6Rs exist in the serum and bind to IL-6 forming an IL-6/sIL-6R complex. Soluble IL-6R (sIL-6R) is produced by two separate mechanisms, firstly by proteolytic cleavage from the surface of neutrophils and secondly by secretion from neutrophils and
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