What makes il 6

IL-6 has also been implicated in autoimmunity. Furthermore, autoimmune phenomena increase with age, in concert with an age-related increase in sIL-6R shedding [ 37 ]. Lissilaa et al. Using antibodies which specifically blocked classical IL-6 signalling and trans signalling pathways, they discovered that the classical IL-6 pathway was both necessary and sufficient for the development of pathogenic Th17 T cells which are implicated in autoimmunity and for the generation of antitype II collagen IgG responses which are associated with disease manifestations in the CIA model.

They also demonstrated in the AIA model that IL-6 trans signalling was responsible for driving local inflammatory responses [ 38 ]. SSc is a disease associated with autoimmune phenomena. Many different autoantibodies are found in SSc see Table 1 , and the autoantibody profile in many cases correlates with clinical manifestations.

There is, however, no convincing evidence for a direct role for autoantibodies in pathogenesis though some investigators have reported that antiendothelial cell antibodies, found in a proportion of patients, are associated with endothelial cell activation [ 39 , 40 ]. Fibroblasts from patients with SSc are phenotypically unique. When isolated and cultured in vitro they continue to produce an excess of collagen [ 42 , 43 ].

IL-6 is a profibrogenic cytokine. It has been shown to either increase or decrease fibroblast proliferation, increase fibroblast collagen, glycosaminoglycan, and tissue inhibitor of metalloproteinases-1 TIMP-1 synthesis, and increase MCP-1 and IL-6 production [ 43 — 48 ]. IL-6 regulates the expression of vascular endothelial growth factor VEGF , an important mediator of angiogenesis and fibrosis which is elevated in patients with SSc [ 49 ].

One case series has indicated that the use of tocilizumab, which blocks IL-6 trans signalling, in 2 patients with diffuse cutaneous SSc dcSSc , one with renal involvement and the other with lung fibrosis, resulted in a decrease in skin thickening as measured by Rodnan skin score and Vesmeter which measures viscoelasticity or hardness of the skin.

In addition, skin biopsies taken before and after tocilizumab treatment indicated a reduction in collagen [ 50 ]. Endothelial activation is thought to be central to the pathogenesis of SSc. There is also evidence for increased endothelial cell apoptosis though corroborative in vivo evidence for this is lacking [ 51 ].

The University of California at Davis line chicken, an animal model for SSc, shows evidence of early endothelial cell apoptosis, preceding the inflammatory cell infiltrate and the development of fibrosis [ 39 — 52 ]. Serum markers of endothelial cell activation, for example, von Willebrand factor vWF , sICAM-1, and sE-selectin are elevated in the serum of patients with SSc and appear to correlate with disease activity [ 53 — 55 ].

Previous studies have shown a role for IL-6 in endothelial cell activation. We have recently shown that SSc serum, in the presence of neutrophils, is capable of increasing endothelial cell activation and apoptosis in an ILdependent manner [ 56 ]. It is postulated that in this circumstance the neutrophils are acting as donors of IL-6R.

In our studies, spiking pooled control serum with IL-6 resulted in increased endothelial cell apoptosis and E-selectin expression in the presence of neutrophils, mimicking the effects of SSc serum. Complement inactivation did not abrogate the effects of SSc serum, neither did the addition of catalase to mop up reactive oxygen species.

The serine protease inhibitor AEBSF partially blocked the effects of SSc serum on endothelial cell apoptosis but did not significantly affect the activation of endothelial cells by SSc serum [ 56 ]. Strategies to remove or block the effects of IL6 in SSc serum including immunodepletion of IL6 and the addition of an anti-IL6 blocking antibody reversed the effects of SSc serum on endothelial cell activation and apoptosis [ 56 ].

Most significantly, however, sgp which specifically blocks IL6 trans signalling abrogated the effects of SSc serum [ 56 ]. IL-6 blockade and specifically the blockade of IL-6 trans-signalling may have merit in the treatment of SSc, a disease that so far lacks treatment options directly targeting the pathogenic mechanism. IL-6 trans signalling is specifically implicated in driving local inflammation and inducing endothelial and fibroblast responses, and therefore targeting this IL-6 signalling pathway may be most profitable in SSc.

However, SSc also has important and possibly pathogenic autoimmune phenomena, and targeting the classical IL-6 signalling pathway may be necessary in order to influence this important aspect of the disease. The currently available drug Tocilizumab targets both the classical and the trans signalling pathways. Other agents are in development which specifically block trans signalling, and they may be useful in mouse models of SSc to delineate which signalling pathway is most important for this disease.

In addition, it is also found in immunohistochemistry samples in both early and late disease and in both dcSSc and lcSSc. Fibroblasts and monocytes isolated from SSc patients autonomously produce IL-6 in vitro.

Early, small-scale nonrandomised controlled trials point to an important role for IL6 in SSc. B-cell depletion results in a decrease in serum IL-6 levels, reflected in a simultaneous reduction in skin score. More importantly, blocking IL-6 trans signalling with Tocilizumab has resulted in an improvement in skin score in 2 patients with diffuse disease.

These data firmly establish IL-6 as an attractive candidate therapeutic target, especially in terms of preventing fibrosis. However, in addition, new and exciting data imply that IL-6 has a role in the endothelial and inflammatory manifestations of this disease, which may make it a potential target in a much broader range of SSc patients with active vascular or inflammatory e.

Studies are being designed to address these important questions; the results are eagerly awaited. Barnes et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.

Read the winning articles. Journal overview. Special Issues. Barnes, 1 Marina E. Anderson, 1 and Robert J. Academic Editor: Lorinda Chung. Received 01 Jun Accepted 21 Jul Published 20 Sep Abstract Interleukin-6 is currently attracting significant interest as a potential therapeutic target in systemic sclerosis SSc. Introduction Systemic sclerosis SSc is a connective tissue disease characterised by fibrosis, vasculopathy, and immunological abnormalities.

Interleukin-6 Biology Interleukin-6 biology is complex. Figure 1. Interleukin-6 trans signalling. IL-6 receptors are expressed on leukocytes including neutrophils, but they are not expressed on tissue-resident cells, for example, endothelial cells. Table 1. Systemic sclerosis-associated autoantibodies, potentially pathogenic antibodies which have been described in a proportion of patients with systemic sclerosis.

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Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. IL-6 expression, IL-6 receptor and its mode of action and signaling.

IL-6 signaling in cell survival, proliferation, metastasis and angiogenesis. Involvement of IL-6 in chronic inflammation, autoimmune diseases and cancer.