Abstract
BackgroundIL-6 is a pleiotropic cytokine that modulates inflammatory responses and plays critical roles in muscle maintenance and remodeling. In the mouse model (mdx) of Duchenne Muscular Dystrophy, IL-6 and muscle inflammation are elevated, which is believed to contribute to the chronic inflammation and failure of muscle regeneration in DMD. The purpose of the current study was to examine the effect of blocking IL-6 signaling on the muscle phenotype including muscle weakness and pathology in the mdx mouse.MethodsA monoclonal antibody against the IL-6 receptor (IL-6r mAb) that blocks local and systemic IL-6 signaling was administered to mdx and BL-10 mice for 5 weeks and muscle function, histology, and inflammation were examined.ResultsIL-6r mAb treatment increased mdx muscle inflammation including total inflammation score and ICAM-1 positive lumens in muscles. There was no significant improvement in muscle strength nor muscle pathology due to IL-6r mAb treatment in mdx mice.ConclusionsThese results showed that instead of reducing inflammation, IL-6 signaling blockade for 5 weeks caused an increase in muscle inflammation, with no significant change in indices related to muscle regeneration and muscle function. The results suggest a potential anti-inflammatory instead of the original hypothesized pro-inflammatory role of IL-6 signaling in the mdx mice.
Highlights
Interleukin 6 (IL-6) is a pleiotropic cytokine that modulates inflammatory responses and plays critical roles in muscle maintenance and remodeling
As IL-6 is likely to have systemic and local effects, we examined these through direct (Suppressor of cytokine signaling 3 (SOCS3), Serum amyloid a (SAA)) and indirect (TNF-alpha, Insulin-like growth factor 1 (IGF1)) targets of IL-6 signaling in target tissues, liver and muscle
Antibody treatment resulted in an 11 % greater strength increase in IL-6 receptor (IL-6r) monoclonal antibody (mAb) treated mdx mice compared to Kh-5 treated mdx mice, though this did not reach statistical significance (6.5 ± 0.2 Newtons per gram of body mass (N/g) versus 5.7 ± 0.3 N/g, P = 0.055)
Summary
IL-6 is a pleiotropic cytokine that modulates inflammatory responses and plays critical roles in muscle maintenance and remodeling. In the mouse model (mdx) of Duchenne Muscular Dystrophy, IL-6 and muscle inflammation are elevated, which is believed to contribute to the chronic inflammation and failure of muscle regeneration in DMD. A hallmark feature of Duchenne Muscular Dystrophy (DMD) is chronic inflammation, it occurs within the muscle of patients and in the mouse model of the disease (mdx). Reducing inflammation in healthy animals where muscle damage has occurred is detrimental to tissue repair [13] and satellite cell activation and differentiation [14]. It seems a reduction, not absence of inflammation is ideal. Specific mediators and markers of the inflammatory process (e.g. IL-6) warrant examination in a dystrophic model
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