Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload (original) (raw)
Related papers
Hepatology, 2005
Hepcidin, a recently discovered iron regulatory peptide, is believed to inhibit the release of iron from absorptive enterocytes and macrophages. Liver hepcidin synthesis is induced in vivo by iron stores and inflammation. The molecular basis of the regulation of hepcidin gene expression by these effectors in hepatocytes is currently unknown, although there is strong evidence that indirect mechanisms are involved. The aims of this study were to gain insight into these mechanisms and to determine to what extent other liver cell types are responsible for transducing the signal by which hepcidin expression is regulated in mouse hepatocytes.
Blood Cells, Molecules, and Diseases, 2008
Iron homeostasis is mainly controlled by the liver-produced hepcidin peptide, which induces the degradation of the ferroportin iron exporter and thus regulates serum iron level. Hepcidin transcription is clearly up-regulated by the pro-inflammatory cytokine IL-6 and down-regulated, in the case of iron depletion, at least via HIF transcription factors. In addition, in vivo iron overload up-regulates hepcidin, but this cannot be reproduced in cell culture or isolated hepatocytes. Here, we investigated the steady state mRNA levels of a series of genes involved in iron metabolism in hepatic HepG2, intestinal Caco-2, and monocyte/macrophage THP-1 cell lines under different iron and culture conditions. Our results showed that iron-saturated transferrin up-regulated hepcidin mRNA synthesis from HepG2 via cross-talk with macrophages or enterocyte cytokine-producing cells, whereas non-transferrin-bound iron down-regulated hepcidin, likely due to missing TfR-iron-transferrin uptake.
Hepcidin and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload
Journal of Hepatology, 2008
Background/Aims: Many patients with hepatic iron overload do not have identifiable mutations and often present with metabolic disorders and hepatic steatosis. Since the pathophysiology of Dysmetabolic Hepatic Iron Overload (DHIO) is still obscure, the aim of this study was to evaluate, in these patients, possible alterations in iron-related molecule expression.
The hepcidin circuits act: Balancing iron and inflammation
Hepatology, 2011
Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidin-mediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-α transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses. Comment Hepcidin is a peptide hormone primarily known as the key regulator of iron homeostasis. This peptide binds the only known cellular iron exporter, ferroportin (Fpn), leading to its internalization and degradation in hepatocytes, enterocytes, and macrophages, preventing iron transport to plasma and causing cellular retention of iron.1 Hepcidin is also an amphipathic peptide with antimicrobial activity similar to the defensin family of proteins.2 Hepcidin expression is up-regulated in response to iron stores, inflammation, and ER stress and inhibited by anemia, erythropoiesis, hypoxia, and oxidative stress.3 Other proposed factors that regulate hepcidin expression include leptin4, p535, estradiol6, and circadian rhythms6. Hepcidin regulation in response to iron stores is mediated via the bone morphogenic protein and Sma-and Mad-related protein (BMP/SMAD) pathway and the HFE/TFR1/TFR2 complex on hepatocytes in response to plasma transferrin levels.3 In the proposed mechanism, soluble BMPs-most notably, BMP6-bind to BMP receptors and the BMP coreceptor, hemojuvelin (HJV), in response to cellular iron levels initiating the phosphorylation of SMAD1/5/8 and subsequent interaction with SMAD4.7 , 8 This complex is then translocated to the nucleus where it binds to BMP-responsive elements (BMP-REs) within the hepcidin promoter up-regulating hepcidin expression. Recently, two new negative regulators of this pathway have been identified, SMAD7, which directly binds the hepcidin promoter to repress transcription9 and transmembrane protease serine 6 (TMPRSS6), which acts by cleaving HJV at the cell membrane to inhibit BMP signaling.10 These negative
Hepcidin generated by hepatoma cells inhibits iron export from co-cultured THP1 monocytes
Journal of Hepatology, 2006
Background/Aims: The antimicrobial peptide hepcidin is generated in the liver and released into the circulation in response to iron, oxygen and inflammatory signals. Hepcidin serves as a hormonal regulator of duodenal iron absorption and iron trafficking in the reticuloendothelial system. The aim of this study is to explore the effects of this regulatory peptide in macrophage iron metabolism.
Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis
American Journal of Physiology-gastrointestinal and Liver Physiology, 2008
One prime feature of alcoholic liver disease (ALD) is iron accumulation in hepatic macrophages/Kupffer cells (KC) associated with enhanced NF-B activation. Our recent work demonstrates a peroxynitritemediated transient rise in intracellular labile iron (ILI) as novel signaling for endotoxin-induced IKK and NF-B activation in rodent KC. The present study investigated the mechanism of KC iron accumulation and its effects on ILI response in experimental ALD. We also tested ILI response in human blood monocytes. Chronic alcohol feeding in rats results in increased expression of transferrin (Tf) receptor-1 and hemochromatosis gene (HFE), enhanced iron uptake, an increase in nonheme iron content, and accentuated ILI response for NF-B activation in KC. Ex vivo treatment of these KC with an iron chelator abrogates the increment of iron content, ILI response, and NF-B activation. The ILI response is evident in macrophages derived from human blood monocytes by PMA treatment but not in vehicle-treated monocytes, and this differentiationassociated phenomenon is essential for maximal TNF-␣ release. PMA-induced macrophages load iron dextran and enhance ILI response and TNF-␣ release. These effects are reproduced in KC selectively loaded in vivo with iron dextran in mice and more importantly aggravate experimental ALD. Our results suggest enhanced iron uptake as a mechanism of KC iron loading in ALD and demonstrate the ILI response as a function acquired by differentiated macrophages in humans and as a priming mechanism for ALD.
Iron overload inhibits BMP/SMAD and IL-6/STAT3 signaling to hepcidin in cultured hepatocytes
PLOS ONE
Hepcidin is a peptide hormone that targets the iron exporter ferroportin, thereby limiting iron entry into the bloodstream. It is generated in hepatocytes mainly in response to increased body iron stores or inflammatory cues. Iron stimulates expression of bone morphogenetic protein 6 (BMP6) from liver sinusoidal endothelial cells, which in turn binds to BMP receptors on hepatocytes and induces the SMAD signaling cascade for transcriptional activation of the hepcidin-encoding HAMP mRNA. SMAD signaling is also essential for inflammatory HAMP mRNA induction by the IL-6/STAT3 pathway. Herein, we utilized human Huh7 hepatoma cells and primary murine hepatocytes to assess the effects of iron perturbations on signaling to hepcidin. Iron chelation appeared to slightly impair signaling to hepcidin. Subsequent iron supplementation not only failed to reverse these effects, but drastically reduced basal HAMP mRNA and inhibited HAMP mRNA induction by BMP6 and/or IL-6. Thus, treatment of cells wi...