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© Borgis - Postępy Nauk Medycznych 7/2012, s. 599-604
*Teresa Jackowska1, 2, Joanna Wójtowicz2
Rola hepcydyny w stanach zapalnych
The role of hepcidin in inflammation**
1Department of Paediatrics, Medical Centre of Postgraduate Education, Warsaw
Head of Department: prof. Teresa Jackowska, MD, PhD
2Clinical Department of Pediatrics, The Bielanski Hospital, Warsaw
Head of Department: prof. Teresa Jackowska, MD, PhD
Niedawne odkrycie hepcydyny znacznie ożywiło badania nad gospodarką żelazem. Działanie hepcydyny, która hamuje wchłanianie i uwalnianie żelaza z komórek, wyjaśniło dotychczasową wiedzę na temat mechanizmów wchłaniania i spichrzania żelaza. Dzięki opisowi stymulacji stężenia hepcydyny stanem zapalnym i jej hamującego wpływu na stężenie żelaza w surowicy, udało się w pełni zrozumieć mechanizmy patologiczne związane między innymi z obniżeniem stężenia żelaza i niedokrwistości w czasie zakażeń i chorób przewlekłych.
W artykule przedstawiono podstawowe cechy hepcydyny, jej działanie, czynniki regulujące jej stężenie, a w szczególności rolę hepcydyny w stanach zapalnych. Przedstawiono potencjalne wykorzystanie wiedzy na temat hepcydyny w procesach diagnostyki różnicowej, np. w rozróżnieniu pomiędzy niedokrwistością chorób przewlekłych, a niedokrwistością z niedoboru żelaza. Ukazano perspektywiczne wykorzystanie substancji osłabiających działanie hepcydyny dla zmniejszenia stanów patologicznych związanych z zapaleniem.
The recent discovery of hepcidin has significantly intensified research on iron metabolism. Hepcidin, which inhibits iron intake and release from cells, has turned out to be a crucial player in the mechanisms of iron absorption and accumulation. Since hepcidin concentration is enhanced during inflammation, and hepcidin lowers the iron concentration itself, it is now more clear how pathologies like hypoferremia and anemia that accompany infections and chronic inflammation occur.
The key issues covered in the article are: basic facts about hepcidin, its physiological function and factors which determine its concentration, followed by an analysis of the role of hepcidin in inflammation. The paper also presents how knowledge about hepcidin may potentially facilitate the process of differential diagnosis, for example: iron-deficiency anemia versus anemia of chronic disease. A list of substances taken into account to be used as therapeutics that would reduce the influence of hepcidin on the iron concentration in chronic inflammation is presented at the end.
The history of discovering hepcidin
In 2000 the LEAP-1 (liver expressed antimicrobial peptide) molecule was isolated from human blood (1). A year later the same peptide was found in human urine, and was called hepcidin, due to the similarity of the amino acid sequence to murine hepcidin produced in the liver (2). Hepcidin was then qualified as belonging to the group of antibacterial peptides, alongside with defensins and protegrins, with regard to its structure that is rich in cysteines, as well as its antifungal and antibacterial activity in in vitro conditions. Thus, its name: hepcidin, meaning produced in the liver and of antibacterial activity (2).
However, it soon turned out that hepcidin is not merely another defensive protein that was discovered, but a central agent unifying the metabolic pathways regulating the iron concentration in the body. Its discovery significantly revived the research on iron metabolism in the last decade and gave a solid basis for using this knowledge in future clinical practice.
The activity of hepcidin
The basic activity of hepcidin is binding to ferroportin, the only protein described to date that transports iron from the cytoplasm to the extracellular space, e.g. to blood. As a result of the binding of hepcidin with ferroportin occurs an internalisation of ferroportin and its degradation, which in consequence leads to a reduction of iron concentration in serum (fig. 1). After the deactivation of ferroportin, iron is accumulated inside cells, e.g. the enterocytes, macrophages, hepatocytes and placenta cells (tab. 1) (3).
Fig. 1. Schema of the impact of hepcidin on a decreased iron absorption/release from effector cells (modified from (3)). The left schema presents the iron release by ferroportin. The right schema presents the activity of hepcidin, which binds to ferroportin, leading to its internalisaton and degradation, which in turn makes the transport of iron to blood impossible.
Table 1. Hepcidin activity.
Hepcidin activity
Inhibiting the release of iron from enterocytes
Inhibiting the release of iron from hepatocytes
Inhibiting the release of iron from macrophages
Inhibiting the release of iron form placenta cells
It has been empirically demonstrated that there is an inversely proportional relationship between the concentration of hepcidin and the concentration of iron in serum. Hepcidin was administered in three different doses to mice, and the observed decrease of iron concentration in serum was proportional to that dose (4). The only peptide active in this respect is the 25-amino acid sequence of hepcidin, as opposed to its metabolites, i.e. the 20- and 22-amino acid peptides. A similar activity is also not present in the precursor peptide for hepcidin i.e. prohepcidin, which was initially regarded as very promising, as it is easier to determine its concentration in body fluids (5).
It has also been demonstrated that there is an inverse relationship between hepcidin and iron concentration, in a clinical study with an iron overload, where the iron was administered orally to the participants. This caused an increased hepcidin concentration in serum (6). The results gave the basis to propose a study on hepcidin concentration as a reliable marker of iron metabolism, e.g. to predict the effectiveness of iron absorption when it is taken orally or to predict the response to treatment with ESA (erythropoesis stimulating agents) (7).
Understanding the metabolic pathways of hepcidin activity related to the effectiveness of iron absorption and accumulation has made it possible to explain the pathophysiological mechanisms of many diseases. Among them are hemochromatoses, where due to a mutation of the metabolic pathways an iron overload in tissue is caused (8) and in syderopenic anemia refractory to orally iron administration, where the iron absorption from the small intestine is inhibited through an excessive transcription of hepcidin (9).
Various mutations that condition the final increased or decreased activity of hepcidin have been described to date based on animal models and clinical cases. A severe iron overload of tissue was related e.g. to a mutation of the HAMP gene that encodes hepcidin in mice (10). Also, mutations of proteins that physiologically lead to an increase in hepcidin secretion (e.g. hemojuvelin knockout) cause a significant decrease in hepcidin concentration, and thus, an increased iron absorption and release (11). On the other hand, an overexpression of hepcidin causes animals to die shortly after birth due to severe anemia (12).
In humans, mutations of genes related to the regulation of hepcidin expression and activity in hemochromatoses have been described (8). In hepatocellular carcinoma, as well as in the Castelman disease, related to an excessive synthesis of interleukin 6 (IL-6), an overproduction of hepcidin was observed (13, 14). An increased or decreased activity of hepcidin may be connected with an abnormal structure of the ferroportin molecule, which affects the effectiveness of hepcidin binding with this protein, as well as the ultimate result of the regulation of iron metabolism.
Factors regulating hepcidin concentration
Four basic groups of factors regulate the hepcidin concentration in serum (tab. 2) (15). The factors responsible for a decreased hepcidin concentration are erythropoiesis and hypoxia. Both mechanisms condition an decreased hepcidin concentration, and thus, a decreased inhibition of iron absorption. Iron then becomes more accessible for the newly created erythrocytes.
Table 2. Four groups of factors that regulate hepcidin concentration (description and symbol explanation in the text).
Factors regulating hepcidin concentration
 Impact on hepcidin
Regulatory factors
(unknown intracellularpathways)
Hypoxia, oxidative stress
(through the factors of HIF and CREBH)
Iron levelin serumIncrease
Transferrin-iron complex (Tf-Fe)
(by SMAD proteins)
(through STAT proteins)
An increased hepcidin concentration, on the other hand, occurs as a result of an increased iron concentration in serum and during inflammation. A decreased iron concentration is observed then.
The impact of erythropoiesis on hepcidin concentration
When erythropoiesis occurs, mediators are created that inhibit the transcription of hepcidin. These are most likely the GDF15 (growth differentiation factor 15) (16) or the TWSG1 (twisted gastrulation protein homolog 1) (17), and they affect the hepatocytes by stimulating the yet unknown intracellular pathway. The concentration of hepcidin also decreases as a result of administering erythropoietin or other agents that stimulate erythropoiesis (ESA) (18).
The impact of tissue hypoxia on hepcidin concentration
As a result of tissue hypoxia, e.g. in anemia, mediators appear that inhibit the transcription of hepcidin. This is oxidative stress, as a result of which in the endoplasmatic reticulum appears the CREBH (cyclic-AMP-responsive-element-binding protein H) (19) as well as factors that lead to an increased HIF (hypoxia-inducible factor) protein concentration. In mice, a mutation of the VHL (von Hippel-Lindau) transcription factor co-occurs with a high HIF concentration, and hence, a decreased hepcidin concentration (20).
Impact of iron concentration in serum on hepcidin concentration
It has been demonstrated that increased iron concentration in serum, metabolically “interpreted” as an increased concentration of the transferrin-iron complex (Tf-Fe), causes an increased hepcidin level, which leads to an inhibition of iron absorption (21). However, the mechanism thanks to which hepcidin concentration is to be regulated by the intra-cellular iron concentration has not been described to date.

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otrzymano: 2012-05-07
zaakceptowano do druku: 2012-06-04

Adres do korespondencji:
*Teresa Jackowska
Klinika Pediatrii Centrum Medyczne Kształcenia Podyplomowego
ul. Marymoncka 99/103, 01-813 Warszawa
tel.: +48 (22) 864-11-67
e-mail: tjackowska@cmkp.edu.pl

Postępy Nauk Medycznych 7/2012
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