Clinical experience with inhibition of interleukin-6

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Interleukin-6

IL-6 is a pleiotropic cytokine with diverse biologic effects [6]. This is reflected by the different names that were assigned to IL-6: interferon b2, IL-1–inducible 26 kD protein, hepatocyte stimulating factor, cytotoxic T cell differentiation factor, B cell differentiation factor, B cell stimulatory factor 2, hybridoma/plasmacytoma growth factor, hepatocyte stimulating factor, monocyte granulocyte inducer type 2, and thrombopoietin. The name IL-6 was assigned once it was appreciated that all

Structure of interleukin-6

IL-6 is a glycoprotein, a 184–amino acid molecule with a molecular weight of 21 to 28 kD depending on posttranslational modification [8]. Alternate splice variants are found in some cell types. It is produced by a wide range of immunocytes and mesenchymal cells including lymphocytes, monocytes, neutrophils, eosinophils, B cells, fibroblasts, synoviocytes, endothelial cells and neurons, adrenal glands, mast cells, keratinocytes, Langerhans cells, astrocytes, and colonic epithelial cells [9].

The interleukin-6 receptor and signal transduction

Human IL-6 receptor (IL-6R) is an 80-kDa transmembrane glycoprotein [10] that binds to IL-6 with low affinity. IL-6R does not have an intracellular signal transduction domain, therefore IL-6/IL-6R engagement alone does not lead to cellular activation, and cell surface expression of IL-6 R does not mean the cell is responsive to IL-6 stimulation. Proteolytic cleavage leads to the release of soluble forms of IL-6R. Soluble IL-6R (sIL-6R) can also bind to circulating IL-6. For cellular activation,

Function of interleukin-6

The diverse biologic activities of IL-6 can be broadly divided into those involved in the immune response and those affected mesenchymal cells.

The effect of IL-6 on the immune response has been studied extensively in vitro. IL-6, also known as B-cell stimulatory/differentiating factor, stimulates B cells to differentiate into plasma cells and the latter to proliferate and produce immunoglobulins [7]. It also stimulates the proliferation and differentiation of T lymphocytes into cytotoxic T

Interleukin-6 in rheumatoid arthritis

IL-6 and other members of the IL-6 superfamily of cytokines could be found in the synovial joints of patients with active RA [24]. They have been implicated in the pathogenesis of joint damage, synovitis, and systemic features of the disease. However, some researchers have argued that based on the in vitro anti-inflammatory effects of IL-6, its role in RA is one of regulation rather than inducing inflammation.

One of the most convincing pieces of evidence that IL-6 plays a pivotal role in the

Blocking interleukin-6 in animal model of rheumatoid arthritis

Animal models are frequently used to study the pathogenesis of RA and to investigate the therapeutic potential of novel therapies. One of the most common models is that of collagen-induced arthritis in DBA/1J mice. When bovine type II collagen is injected into these animals, they develop an inflammatory and destructive arthritis resembling RA. The effect of IL-6 blockade was tested in this animal using a monoclonal antibody to IL-6R [33]. A single dose (0.5–8 mg) of rat antimouse IL-6 receptor

Blocking interleukin-6 in rheumatoid arthritis

The encouraging results from blocking IL-6 in animal models of RA prompted investigators to assess this strategy in patients with RA. Five patients with RA were treated in an open-label study with a murine anti–IL-6 monoclonal antibody, B-E8, which was administered intravenously once a day for 10 consecutive days at a dose of 10 mg/kg [35]. There was a rapid and significant clinical improvement in pain and morning stiffness. The number of tender and swollen joints reduced rapidly during the

Summary

IL-6 is an important cytokine in maintaining synovial inflammation. Interruption of IL-6 signal transduction by monoclonal antibody to IL6-R and MRA reduced synovial inflammation. MRA appears to be well tolerated and holds promise as a potential new therapy for RA.

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      IL-6 is produced by a variety of cell types such as lymphocytes (including T and B cells), monocytes, fibroblasts, endothelial cells, osteoblasts, and synovial cells. It is involved in diverse physiological functions: from T-cell activation and stimulation of hematopoietic precursor cell proliferation/differentiation to induction of immunoglobulin secretion, and from initiation of hepatic acute-phase protein synthesis to bone remodeling.6,7 Perhaps unsurprisingly, given its involvement in multiple physiological processes, elevation of IL-6 due to deregulated production has been implicated in the pathology of various inflammatory diseases such as rheumatoid arthritis (RA), Castleman's disease, juvenile idiopathic arthritis, and Crohn's disease.8

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