Anti-interleukin-6 receptor antibody (MR16-1) promotes muscle regeneration via modulation of gene expressions in infiltrated macrophages

• Published in: Biochimica et biophysica acta Vol. 1840; no. 10; pp. 3170 - 3180
• Main Authors: Fujita, Ryo, Kawano, Fumimori, Ohira, Takashi, Nakai, Naoya, Shibaguchi, Tsubasa, Nishimoto, Norihiro, Ohira, Yoshinobu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2014
• Subjects: Animals; Anti-mouse IL-6 receptor (IL-6R) antibody; antibodies; Antibodies, Monoclonal - pharmacology; arginase; Arginase - genetics; Arginase - metabolism; Fibrosis; Gene Expression Regulation - drug effects; genes; half life; interleukin-10; Interleukin-10 - genetics; Interleukin-10 - metabolism; interleukin-6; macrophages; Macrophages - metabolism; Macrophages - pathology; Mice; Mice, Knockout; muscle development; Muscle injury; Muscle Proteins - biosynthesis; Muscle Proteins - genetics; Muscle regeneration; Muscle, Skeletal - injuries; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; muscles; phosphorylation; Rats; Receptors, Interleukin-6 - antagonists & inhibitors; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; Regeneration - drug effects; Regeneration - genetics; signal transduction; skeletal muscle; transactivators; Muscle injury; MR16-1; LMD; Anti-mouse IL-6 receptor (IL-6R) antibody; CTX; STAT3; Fibrosis; Muscle regeneration
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.01.014

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. The MR16-1 was administered i.p. immediately after cardiotoxin (CTX)-induced muscle damage on mice. MR16-1 administered i.p. was observed only to the damaged muscle. This delivered MR16-1 was dramatically decreased from 3 to 7days 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 3days 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. 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. General significance: 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. •The i.p. administered MR16-1 was detected in the damaged muscle.•The remaining MR16-1 to the damaged muscle was correlated with IL-6R levels.•The treatment with MR16-1 resulted in reduced pSTAT3 level in the macrophages.•The MR16-1 treatment decreased fibrosis-related genes in the macrophages.•MR16-1 treatment facilitated the muscle regeneration via immune modulation.