Interleukin-6

Overview

Among the mediators of inflammation that are expressed in muscles affected by PM, IL-6 is of particular interest. IL-6 has been found to be expressed in infiltrating mononuclear cells in affected muscles . Previous studies have shown increased serum levels of IL-6 and increased levels of IL-6 messenger RNA (mRNA) in the muscles of patients with PM/DM . Functionally, it is a modulator of leukocyte recruitment as well as a B cell stimulator. It also promotes differentiation of cytotoxic T cells as well as Th17 cells , which have been established as critical for the development of autoimmune disease models.(1)

Trials

The skeletal muscle C protein is a myosin-binding protein that regulates muscle filament components functionally and structurally . CIM can be induced by a single injection of its fragments into C57BL/6 (B6) mice. Unlike EAM, CIM has an abundance of perforin-positive CD8 T cells infiltrating in the endomysial sites, some of which invade non-necrotic muscle fibers. Class I major histocompatibility complex (MHC) expression on muscle fibers is up-regulated. CD8 T cell–depleted mice are resistant to CIM induction. Thus, the pathologic process in CIM mimics the known pathologic process in PM , although we are not yet certain if the skeletal muscle C protein is recognized as an autoantigen in human PM. (1)

Of note, the activity of most of these diseases was attenuated in IL-6–null mice and by blockade of the IL-6 signaling pathway . Since the presence of IL-6 in addition to transforming growth factor β (TGFβ) is essential for Th17 cell differentiation , it is reasonable to assume that IL-6 blockade exerted its effects by suppressing Th17 cell development.(2)

Similar to the muscles of patients with PM, the muscles of mice with CIM in several studies had infiltration of mononuclear cells expressing IL-6. Hosts defective in IL-6 were resistant to CIM induction, while those defective in IL-17A were fully susceptible. Anti–IL-6R monoclonal antibody administration ameliorated myositis not only in a preventive protocol but, more importantly, in a therapeutic one. The antibody should inhibit pathologic pathways evoked by IL-6 production that could be triggered by adjuvants in CIM and might be triggered by another pathologic process in PM.(2)

It was interesting to note that the therapeutic effect of anti–IL-6R antibodies seemed greater than their preventive effect. However, this might be because mice in the therapeutic protocol had less severe CIM. It is also possible that the acute elevation of serum IL-6 that occurred within 24 hours of CIM immunization (data not shown) might attenuate the effect of the anti–IL-6R antibodies in the preventive protocol.(3)

What’s Next

It should be noted that the same antibodies had to be administered in a large amount to suppress CIA, an animal model of RA. Nevertheless, tocilizumab has been used successfully for the treatment of RA . Thus, in the case of anti–IL-6R antibodies, the dose required in murine experiments does not predict feasibility in human use. We believe that our findings in the CIM model provide a rationale for considering clinical trials of IL-6– blocking agents to treat patients with PM.(1)(2)

Because IL-6 blockade was expected to constitute a novel strategy for the treatment of such diseases, tocilizumab, a humanized anti-IL-6 receptor antibody (anti-IL-6RAb), was developed. Clinical trials have demonstrated the efficacy of anti-IL-6RAb for patients with rheumatoid arthritis, Castleman's disease, and juvenile idiopathic arthritis, resulting in approval of this innovative biologic for the treatment of these diseases, and it can be expected to become a novel drug for various other autoimmune and inflammatory diseases like PM. (4)

 

Footnotes:

1. Naoko O .Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A .. Arthritis & Rheumatism .Volume 60, Issue 8, pages 2505–2512, August 2009. viewLundberg IE .The role of cytokines, chemokines, and adhesion molecules in the pathogenesis of idiopathic inflammatory myopathies. Rheumatol Rep. 2000 Jun;2(3):216-24.view

2. Notarnicola A. Correlation between serum levels of IL-15 and IL-17 in patients with idiopathic inflammatory myopathies. Scandinavian Journal of Rheumatology .Volume 44, Issue 3, 2015 . view

3. Ingrid L. Decreased expression of interleukin-1α, interleukin-1β, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis. Arthritis & Rheumatism Volume 43, Issue 2, pages 336–348, February 2000. view

 

4. Tanaka, T. Therapeutic Targeting of the Interleukin-6 Receptor.Annual Review of Pharmacology and Toxicology.Vol. 52: 199-219 (Volume publication date February 2012) . http://www.annualreviews.org/doi/abs/10.1146/annurev-pharmtox-010611-134715