Interleukin (IL)-6 has been studied since its discovery for its role in health and diseases. It is one of the most important pro-inflammatory cytokines. IL-6 was reported as an exacerbating factor in coronavirus disease. In recent years, it has become clear that the function of muscle-derived IL-6 is different from what has been reported so far. Exercise is accompanied by skeletal muscle contraction, during which, several bioactive substances, collectively named myokines, are secreted from the muscles. Many reports have shown that IL-6 is the most abundant myokine. Interestingly, it was indicated that IL-6 plays opposing roles as a myokine and as a pro-inflammatory cytokine. In this review, we discuss why IL-6 has different functions, the signaling mode of hyper-IL-6 via soluble IL-6 receptor (sIL-6R), and the involvement of soluble glycoprotein 130 in the suppressive effect of hyper-IL-6. Furthermore, the involvement of a disintegrin and metalloprotease family molecules in the secretion of sIL-6R is described. One of the functions of muscle-derived IL-6 is lipid metabolism in the liver. However, the differences between the functions of IL-6 as a pro-inflammatory cytokine and the functions of muscle-derived IL-6 are unclear. Although the involvement of myokines in lipid metabolism in adipocytes was previously discussed, little is known about the direct relationship between nonalcoholic fatty liver disease and muscle-derived IL-6. This review is the first to discuss the relationship between the function of IL-6 in diseases and the function of muscle-derived IL-6, focusing on IL-6 signaling and lipid metabolism in the liver.
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