Interleukin-6 Contributes to Hepcidin MRNA Increase in Response to Exercise

The iron regulatory peptide hormone hepcidin has been proposed to participate in training-induced iron deficiency. Plasma and urinary hepcidin increase in response to one bout of prolonged exercise, a condition also known to increase plasma interleukin-6 (Il-6). Because Il-6 activates hepcidin transcription and expression during inflammation, our aim was to study the role of this cytokine in hepatic hepcidin mRNA expression during exercise and recovery. We used a rodent model of exhaustive running exercise, where rats were treated or not with cyclosporin A (CsA), a calcineurin inhibitor shown to blunt plasma Il-6 during exercise. Despite similar running intensity and duration, animals treated with CsA had 50% lower plasma Il-6 concentrations at the end of exercise. The concomitant rise in hepatic mRNA levels of two Il-6 responsive genes, suppressor of cytokine signaling (SOCS) 3 and Il-6 receptor alpha, was blunted in CsA-treated group. Finally, hepcidin mRNA levels increased in response to exercise, peaking 2h later, but peak values were significantly lower in CsA group compared to control group. This result strongly suggests that plasma Il-6 is involved in exercise-induced increase of hepcidin gene expression.