The Soluble Interleukin 6 Receptor: Advanced Therapeutic Options in Inflammation

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Abstract

Interleukin (IL)-6 binds to IL-6R and the complex of IL-6 and IL-6R associates with the receptor subunit gp130, which initiates signaling. gp130 is expressed on all cells. IL-6R is cleaved by the ADAM17, generating a soluble IL-6R (sIL-6R). The sIL-6R binds IL-6 and the complex of IL-6 and sIL-6R binds to gp130 even on cells that do not express IL-6R. This process, which has been called IL-6 trans-signaling, increases the spectrum of target cells for IL-6. We generated a protein, sgp130Fc, which inhibits IL-6 trans-signaling without affecting IL-6 classic signaling. Using the sgp130Fc protein we demonstrated that IL-6 classic signaling is antiinflammatory and protective, whereas IL-6 trans-signaling is proinflammatory. Blocking IL-6 trans-signaling does not compromise the defense of the body against bacterial infections. We suggest that sgp130Fc is a superior agent as compared to IL-6 or IL-6R antibodies to block IL-6. The sgp130Fc protein is in phase II clinical trials.

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Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin.

T Hirano, K Yasukawa, H Harada … (1986)

When stimulated with antigen, B cells are influenced by T cells to proliferate and differentiate into antibody-forming cells. Since it was reported that soluble factors could replace certain functions of helper T cells in the antibody response, several different kinds of lymphokines and monokines have been reported in B-cell growth and differentiation. Among these, human B-cell differentiation factor (BCDF or BSF-2) has been shown to induce the final maturation of B cells into immunoglobulin-secreting cells. BSF-2 was purified to homogeneity and its partial NH2-terminal amino-acid sequence was determined. These studies indicated that BSF-2 is functionally and structurally unlike other known proteins. Here, we report the molecular cloning, structural analysis and functional expression of the cDNA encoding human BSF-2. The primary sequence of BSF-2 deduced from the cDNA reveals that BSF-2 is a novel interleukin consisting of 184 amino acids.

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Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling.

Simon A. Jones, Jürgen Scheller, Stefan Rose-John (2011)

The successful treatment of certain autoimmune conditions with the humanized anti-IL-6 receptor (IL-6R) antibody tocilizumab has emphasized the clinical importance of cytokines that signal through the β-receptor subunit glycoprotein 130 (gp130). In this Review, we explore how gp130 signaling controls disease progression and examine why IL-6 has a special role among these cytokines as an inflammatory regulator. Attention will be given to the role of the soluble IL-6R, and we will provide a perspective into the clinical blockade of IL-6 activity in autoimmunity, inflammation, and cancer.

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The role of interleukin-6 signaling in nervous tissue.

Michelle Rothaug, Christoph Becker-Pauly, Stefan Rose-John (2016)

The cytokine interleukin-6 (IL-6) plays a critical role in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. Profound neuropathological changes, such as multiple sclerosis (MS), Parkinson's and Alzheimer's disease are associated with increased IL-6 expression in brain. Increased nocturnal concentrations of serum IL-6 are found in patients with impaired sleep whereas IL-6-deficient mice spend more time in rapid eye movement sleep associated with dreaming. IL-6 is crucial in the differentiation of oligodendrocytes, regeneration of peripheral nerves and acts as a neurotrophic factor. It exerts its cellular effects through two distinct pathways which include the anti-inflammatory pathway involving the membrane-bound IL-6 receptor (IL-6R) expressed on selective cells, including microglia, in a process known as classical signaling that is also critical for bacterial defense. In classical signaling binding of IL-6 to the membrane-bound IL-6R activates the β-receptor glycoprotein 130 (gp130) and subsequent down-stream signaling. The alternative, rather pro-inflammatory pathway, shown to mediate neurodegeneration in mice, termed trans-signaling, depends on a soluble form of the IL-6R that is capable of binding IL-6 to stimulate a response on distal cells that express gp130. A naturally occurring soluble form of gp130 (sgp130) has been identified that can specifically bind and neutralize the IL-6R/IL-6 complex. Thus, trans-signaling is blocked but classical signaling is completely unaffected. A modified, recombinant dimerized version of sgp130 (sgp130Fc) has successfully been used to block inflammatory processes in mice and may also be used in the clarification of IL-6 trans-signaling in neurological diseases.