STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation

Ahmad

Laboratory Investigation

2010

The source of circulating erythropoietin (EPO), the mediators and the mechanisms involved in the upregulation of EPO gene expression during acute-phase reaction are still poorly understood. Acute-phase reaction was induced by either intramuscular turpentine oil (TO) or intraperitoneal lipopolysaccharide (LPS) administration into wild-type and interleukin (IL)-6 knockout (KO) mice. Animals were killed at different time points and blood, liver and muscle tissue were collected. Serum levels of EPO were measured by enzyme-linked immunoadsorbent assay; liver and injured muscle samples were processed for RNA isolation and for protein analysis. EPO, hypoxia-inducible factors 1a and 2a (HIF-1a and HIF-2a) mRNA were analyzed by RT-PCR and the protein levels were analyzed by western blot and electrophoretic mobility shift assay. HIF-1a and HIF-2a localization was performed through immunofluorescence staining. EPO, HIF-1 and HIF-2 gene and protein expression levels were also analyzed in isolated mouse hepatocytes after stimulation with IL-6. In the wild-type animals, EPO serum levels increased dramatically at 12 h after the insults together with the hepatic gene expression. In TO-treated animals, the EPO gene expression reached an 8.2-fold increase at 12 h, and in LPS-treated mice a similar induction was recorded at 6 h (about 4.5-fold increase). In the IL-6KO strain, the upregulation after the inflammatory stimuli was much lower (only 2.0-fold increase). A progressive upregulation of HIF-1a and HIF-2a was detectable until 6 h after the insults, but only HIF-1a upregulation was reduced in IL-6KO mice. In isolated hepatocytes, stimulation with a single dose of IL-6 induced a nuclear accumulation of HIF-1a, in parallel with an increase of EPO mRNA. No effect on HIF-2a expression was found. IL-6 appears to be the main regulator of EPO gene expression and a major contributor for HIF-1a induction in hepatocytes and Kupffer cells during acute-phase response. The increase of HIF-2a, predominantly expressed in endothelial cells and fibroblast-like cells, seems not to be affected by the lack of IL-6.

Section: Discussionmentioning

confidence: 99%

Cellular and molecular mechanisms regulating the hepatic erythropoietin expression during acute-phase response: a role for IL-6

Ahmad

Laboratory Investigation

2010

“…In humans, the ERFE ortologue encoded by the gene FAM132B seems also involved in hepcidin suppression under conditions of increased erythropoiesis [32,33], although in combination with other factors still poorly characterized [23]. Finally, inflammation strongly stimulates hepcidin synthesis through several interleukins (IL), mainly IL-6 [34] and IL-1β [35]. In acute inflammatory conditions hepcidin release from hepatocytes increases rapidly (within few hours) and exponentially (by more than 10-40-folds) [36,37].…”

Section: Pathophysiological Advances In Iron Metabolismmentioning

confidence: 99%

Modern iron replacement therapy: clinical and pathophysiological insights

et al. 2017

Iron deficiency, with or without anemia, is extremely frequent worldwide, representing a major public health problem. Iron replacement therapy dates back to the seventeenth century, and has progressed relatively slowly until recently. Both oral and intravenous traditional iron formulations are known to be far from ideal, mainly because of tolerability and safety issues, respectively. At the beginning of this century, the discovery of hepcidin/ferroportin axis has represented a turning point in the knowledge of the pathophysiology of iron metabolism disorders, ushering a new era. In the meantime, advances in the pharmaceutical technologies are producing newer iron formulations aimed at minimizing the problems inherent with traditional approaches. The pharmacokinetic of oral and parenteral iron is substantially different, and diversities have become even clearer in light of the hepcidin master role in regulating systemic iron homeostasis. Here we review how iron therapy is changing because of such important advances in both pathophysiology and pharmacology.

“…In fact, pro-inflammatory cytokines, such as interleukin-6, but also the adipokine leptin, stimulate hepcidin transcription through JAK-STAT3 interactions. 4,5 Three recent studies have shown that, both in obese women and in obese children, serum hepcidin levels were significantly higher compared with normal weight controls and have focused on the hepcidin-mediated inhibition of dietary iron absorption in obese patients. [6][7][8] To gain insight into the link between obesity and hepcidin, we performed an intervention study in a group of obese children and evaluated if body mass index (BMI) decrease may reduce circulating hepcidin levels, increasing, therefore, iron absorption and improving iron status.…”

Section: Introductionmentioning

confidence: 99%

Effect of body mass index reduction on serum hepcidin levels and iron status in obese children

et al. 2010

Iron deficiency has been linked to obesity. Hepcidin is the main regulator of iron homeostasis and is higher in obese children compared to controls. To gain insight into the link between obesity and hepcidin, we performed an intervention study in 15 obese children. These children were subjected to a 6-month weight loss program and underwent physical examination and iron status and absorption as well as hepcidin, interleukin-6 and leptin serum levels evaluation at baseline and after the weight loss program. After the program all children reduced their body mass index standard deviation score (BMI SDS) of at least 0.5. We observed a significant decrease in hepcidin (P ¼ 0.003) and leptin levels (P ¼ 0.005), and a significant increase in iron absorption (P ¼ 0.02). A direct correlation between the measure of hepcidin and leptin reduction was observed and this correlation appeared significant (r 2 ¼ 0.33, P ¼ 0.003) when adjusted for interleukin-6 and BMI SDS variations. In conclusion, we have shown that, in obese children, BMI reduction is associated with hepcidin reduction, potentially improving iron status and absorption. Implications of these findings could be considered in the management of obese children with poor iron status.