Exercise-induced liver chemokine CXCL-1 expression is linked to muscle-derived interleukin-6 expression

Non-technical summary Exercise is known to stimulate the production of various exercise factors including the well-described muscle-derived interleukin-6 (IL-6). We show that exercise causes a massive expression of the chemokine CXCL-1 in serum, in skeletal muscle and especially in the liver. Furthermore we find that this exercise-induced liver CXCL-1 expression is regulated by IL-6 and that muscle-derived IL-6 is capable of stimulating liver CXCL-1 expression. Such knowledge of the regulation of exercise factors contributes to the understanding of how the liver and muscle communicate in response to exercise.The chemokine CXC ligand-1 (CXCL-1) is a small cytokine that elicits effects by signalling through the chemokine receptor CXCR2. CXCL-1 has neutrophil chemoattractant activity, is involved in the processes of angiogenesis, inflammation and wound healing, and may possess neuroprotective effects. The aim of this study was to unravel the mechanisms whereby CXCL-1 is regulated by exercise in mice. After a single bout of exercise, CXCL-1 protein increased in serum (2.4-fold), and CXCL-1 mRNA in muscle (6.5-fold) and liver (41-fold). These increases in CXCL-1 were preceded by increases in serum interleukin-6 (IL-6) and muscle IL-6 mRNA. In contrast, exercise-induced regulation of liver CXCL-1 mRNA expression was completely blunted in IL-6 knockout mice. Based on these findings, we examined the possible existence of a muscle-to-liver axis by overexpressing IL-6 in muscles. This resulted in increases in serum CXCL-1 (5-fold) and liver CXCL-1 mRNA expression (24-fold) compared with control. Because IL-6 expression and release are known to be augmented during exercise in glycogen-depleted animals, CXCL-1 and IL-6 expression were examined after exercise in overnight-fasted mice. We found that fasting significantly augmented serum CXCL-1, and CXCL-1 expression in liver and muscle. Taken together, these data indicate that liver is the main source of serum CXCL-1 during exercise in mice, and that the CXCL-1 expression in the liver is regulated by muscle-derived IL-6.