Overview

Interleukin (IL)-6 is a typical cytokine featuring redundancy and pleiotropic activity. It contributes to host defense against pathogens, but dysregulation of IL-6 production plays a significant pathological role in various autoimmune and inflammatory diseases. 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.(1)

(The classic IL-6 signaling system. IL-6 is capable of activating two major pathways: the STAT3 and MAPK pathways. These pathways activate downstream signaling of IL-6R, leading to induction of a variety of gene expression. This signaling also induces SOCS1 and SOCS3 expression, which in turn suppress the IL-6 signaling pathway.)(1)

(Regulatory mechanisms of IL-6 production. Regnase-1 promotes degradation of IL-6 mRNA, whereas Arid5a counteracts this by destabilizing the effect of Regnase-1. The functional balance between Arid5a and Regnase-1 determines IL-6 mRNA stability. IRAK1, IL-1 receptor-associated kinase 1; NEMO, NF-κB essential modulator; TRAF6, TNF receptor-associated factor 6; Ub, ubiquitination.)(1)

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.(2)

Although rat anti-mouse IL-6 receptor (IL-6R) antibody (MR16-1) has been reported to effectively ameliorate various tissue damages, its effect on skeletal muscle regeneration has not been determined. Moreover, the localization, persistence and duration of action of this reagent in damaged tissues after systemic administration have not been assessed.(3)

In murine models of autoimmune diseases, anti-IL-6RAb induces Treg and inhibits Th17 and/or Th1 differentiation, indicating that anti-IL-6RAb may be able to repair Th17/Treg imbalance in human diseases as well.(3)

Trials

MR16-1 administered i.p. was observed only to the damaged muscle. This delivered MR16-1 was dramatically decreased from 3 to 7 days post-injury concomitantly with a reduction of IL-6R expression. This reduction of the MR16-1 level in the damaged muscle was not rescued by additional administration of MR16-1, suggesting the short half-life of MR16-1 was not the factor for the remaining levels. In addition, a significant inhibitory effect of MR16-1 on phosphorylation of the signal transducer and activator of transcription 3 was observed in the macrophage-enriched area of damaged muscle 3 days after injury. Finally, the acceleration of muscle regeneration observed at day 7 post-injury following MR16-1 treatment was associated with reduced expression of fibrosis-related genes, such as interleukin-10 and arginase, in the infiltrated macrophages. (4)

Relevance

These results suggest that MR16-1 which was found primarily localized in infiltrated macrophages in the damaged muscle might facilitate muscle regeneration via immune modulation.

These findings are deemed to provide further insight into the understanding not only of MR16-1 treatment on muscle regeneration, but also of the other anti-cytokine treatment on the cytokine-related disease.

 

Footnotes

1. Kimura A.,2009. Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J. Exp. Med. 206:2027.Abstract/FREE Full Text

 

2. Nguyen N. T.2013. The roles of aryl hydrocarbon receptor in immune responses. Int. Immunol. 25:335.Abstract/FREE Full Text

3. Veldhoen M., 2008. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106.CrossRefMedlineWeb of ScienceGoogle Scholar

4. Ryo F. Anti-interleukin-6 receptor antibody (MR16-1) promotes muscle regeneration via modulation of gene expressions in infiltrated macrophages.Biochimica et Biophysica Acta (BBA) - General Subjects. Volume 1840, Issue 10, October 2014, Pages 3170–3180. http://www.sciencedirect.com/science/article/pii/S0304416514000166