Abstract
BackgroundInterleukin 15 (IL-15) is thought to be abundant in the skeletal muscle under steady state conditions based on RNA expression; however, the IL-15 RNA level may not reflect the protein level due to post-transcriptional regulation. Although exogenous protein treatment and overexpression studies indicated IL-15 functions in the skeletal muscle, how the skeletal muscle cell uses IL-15 remains unclear. In myositis patients, IL-15 protein is up-regulated in the skeletal muscle. Given the supporting role of IL-15 in CD8+ T-cell survival and activation and the pathogenic role of cytotoxic CD8+ T cells in polymyositis and inclusion-body myositis, we hypothesize that IL-15 produced by the inflamed skeletal muscle promotes myositis via CD8+ T cells.MethodsExpression of IL-15 and IL-15 receptors at the protein level by skeletal muscle cells were examined under steady state and cytokine stimulation conditions. The functions of IL-15 in the skeletal muscle were investigated using Il15 knockout (Il15−/−) mice. The immune regulatory role of skeletal muscle IL-15 was determined by co-culturing cytokine-stimulated muscle cells and memory-like CD8+ T cells in vitro and by inducing autoimmune myositis in skeletal-muscle-specific Il15−/− mice.ResultsWe found that the IL-15 protein was not expressed by skeletal muscle cells under steady state condition but induced by tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) stimulation and expressed as IL-15/IL-15 receptor alpha (IL-15Rα) complex. Skeletal muscle cells expressed a scanty amount of IL-15 receptor beta (IL-15Rβ) under either conditions and only responded to a high concentration of IL-15 hyperagonist, but not IL-15. Consistently, deficiency of endogenous IL-15 affected neither skeletal muscle growth nor its responses to TNF-α and IFN-γ. On the other hand, the cytokine-stimulated skeletal muscle cells presented antigen and provided IL-15 to promote the effector function of memory-like CD8+ T cells. Genetic ablation of Il15 in skeletal muscle cells greatly ameliorated autoimmune myositis in mice.ConclusionsThese findings together indicate that skeletal muscle IL-15 directly regulates immune effector cells but not muscle cells and thus presents a potential therapeutic target for myositis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-015-0058-2) contains supplementary material, which is available to authorized users.
Highlights
Interleukin 15 (IL-15) is thought to be abundant in the skeletal muscle under steady state conditions based on RNA expression; the IL-15 RNA level may not reflect the protein level due to post-transcriptional regulation
Considering that the level of IL-15 RNA may not reflect the level of protein due to post-transcriptional regulations [31] and that the usage of IL-15 by skeletal muscle cells has not been studied, we examined the expression of IL-15 and its receptors at the protein level in skeletal muscle cells under steady state and cytokinestimulated conditions
Given the presence of posttranscriptional regulation of IL-15 expression and that all circulating IL-15 are in complex with IL-15Rα [9], we examined the expression of IL-15/IL-15Rα complex protein by skeletal muscle cell under the two conditions mentioned above
Summary
Interleukin 15 (IL-15) is thought to be abundant in the skeletal muscle under steady state conditions based on RNA expression; the IL-15 RNA level may not reflect the protein level due to post-transcriptional regulation. Exogenous protein treatment and overexpression studies indicated IL-15 functions in the skeletal muscle, how the skeletal muscle cell uses IL-15 remains unclear. Expression of Il15 mRNA is up-regulated along myoblast differentiation [11]. Previous studies showed that exogenous treatment or overexpression of IL-15 promotes myoblast differentiation and muscle hypertrophy and ameliorates muscle wasting in cancer cachexia [12,13,14,15,16]. Whereas skeletal-muscle-specific overexpression or systemic infusion of IL-15 induces skeletal muscle atrophy in vivo [17,18,19]. The function of IL-15 in the skeletal muscle under non-disease conditions remains elusive
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