These levels were almost double those in previous reports. In line with these findings was the observation of decreased serum iron levels, reflecting iron consumption for increased hemoglobin and erythropoietic cell output.[21] This demand for systemic iron was followed by a compensatory increase in transferrin

levels observed at day 4 in our study. It cannot be ruled out that these findings are a result of the combination of exercise, which could alter muscle iron accumulation and myoglobin homeostasis, and hypoxia. However, most of the findings in this study are in agreement with previous literature from both humans and experimental animals using an experimental setting without physical exertion.[4, 19] In previous studies, mediators of iron homeostasis learn more have been investigated independently under high-altitude conditions. Hypoxia caused an increase of circulating IL-6,[23] whereas serum hepcidin levels were suppressed under these conditions.[1, 21, 24] In line with these findings, the measured IL-6 serum levels in our study were increased, indicating a subtle systemic inflammatory response, which could be slightly attenuated as expected by treatment with dexamethasone. Suppression of hepcidin expression represents the mechanistic link between

hypoxia and the observed changes in systemic iron availability. However, hepcidin suppression at high altitude is not driven by a reduction in iron Selleck I BET 762 stores.[25] Despite the up-regulation of IL-6 as an activator of HAMP gene expression, Phosphoprotein phosphatase the clearance of serum hepcidin levels under hypoxic conditions indicates a dominant-negative regulatory (iron-independent) impact of hypoxia-induced erythropoiesis over inflammatory cytokines. This could be based either on

direct hypoxia-mediated effects on hepcidin expression, or be a consequence of hypoxia-induced erythropoiesis and iron consumption for heme synthesis with a subsequent decrease of circulating iron levels.[32] Our data are in concert with the report of Huang et al.[26] which showed that the erythropoietic drive might inhibit both inflammatory and iron-sensing pathways in mice. Nonetheless, cytokines such as IL-6 can promote iron retention in macrophages by hepcidin-independent pathways, which would also result in low serum iron levels.[27] Such changes are always paralleled by increased circulating ferritin levels. However, the opposite, namely, decreased serum ferritin levels, were observed in our study, thus ruling out IL-6-mediated iron retention under hypoxic conditions. This response to hypoxia was even present in subjects with elevated baseline transferrin saturation or ferritin levels. However, we cannot exclude the presence of a genetic predisposition for later clinically relevant hemochromatosis (e.g., C282Y homozygotes) in these subjects.