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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
Streszczenie
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.
Summary
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
ErythropoiesisDecrease
GDF15, TWSG1, ESA
(unknown intracellularpathways)
HypoxiaDecrease
Hypoxia, oxidative stress
(through the factors of HIF and CREBH)
Iron levelin serumIncrease
Transferrin-iron complex (Tf-Fe)
(by SMAD proteins)
InflammationIncrease
interleukin-6
(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.
There exist disease states where the final hepcidin concentration is influenced by different groups of a mutually opposing activity. The most frequently quoted ones include hemolytic diseases, especially thalassemia, where the significantly stimulated erythropoiesis accompanies an increased hemolysis. On the one hand, erythropoiesis, according to the above principles, should have an inhibitory effect, but on the other hand, the increased levels of circulating iron should stimulate the transcription of hepcidin. However, it has been demonstrated that the factors accompanying erythropoiesis play a dominant role here, and despite the high concentration of iron, an inhibition of hepcidin activity occurs, thus increasing the pathological iron overload of tissue in patients with thalassemia.
The impact of inflammation on hepcidin concentration
Low iron concentration in blood serum due to inflammation is a commonly known effect. The mechanism responsible for this effect had not been known until the impact of inflammation on increased hepcidin concentration was understood. Clinical observations were explained based on two experimental models.
In the first model the inflammation was induced by injecting turpentine into rats – causing inflammation and increased hepcidin concentration (22). What is significant, in knockout animals that from nature did not produce hepcidin or interleukin 6 (IL-6), a decreased iron concentration in this mechanism was not observed.
In the other model, used in both in vivo and in vitro conditions, the inflammation was induced using lipopolysaccharide (LPS) (23). Hepcidin expression was increased after adding LPS to a culture of human hepatocytes. The same effect on these cells was caused by a medium which was transferred from over monocytes that were previously stimulated with LPS. It turned out that the described effects were totally inhibited after adding antibodies against IL-6 to the culture, which again indicated interleukin as the mediator in increasing hepcidin concentration in inflammation. Similar effects were obtained in vivo by injecting LPS into mice or administering it intravenously to humans. In the latter case, as expected, a significant decrease of iron concentration was observed, accompanied by a significantly higher hepcidin concentration.
Pro-inflammatory interleukins other than IL-6 were also studied with regard to their impact on the regulation of hepcidin concentration. A correlation between hepcidin concentration and the concentrations of e.g. TNF-α or INF-γ was not observed (23). The dominant role of IL-6 in regulating hepcidin concentration was also confirmed in observations of the pathophysiological mechanisms in Castelman disease, where a significant increase in hepcidin concentration occurs, caused by an excess of IL-6 produced by stimulated lymphocytes.
The correlation between inflammation and hepcidin level was described in many diseases with chronic inflammation. Studies have demonstrated a relation between the activity of the Crohn’s disease, the IL-6 concentration, the hepcidin concentration and the anemia, caused by it due to iron deficiency (24). The anemia occurring in chronic kidney disease depends not only on a lower erythropoietin concentration, but also on the activity of hepcidin intensified by the inflammation (25). It has also been demonstrated that even a less severe inflammation in fat tissue increases the hepcidin level and is the critical mechanism of anemia in obese persons (26).
In bacterial infections an increased hepcidin level is also observed, e.g. it is a crucial factor causing anemia in patients with sepsis (27). A number of, until now contradictory, study results are provided by analyses of the correlations between the active infections, e.g. Plasmodium spp., Helicobacter pylori, parasitic infestation and hepcidin concentration (28, 29).
The small, dense structure of the hepcidin molecule, rich in cysteines and disulphide bridges, which makes it similar to other defensive proteins, e.g. defensins and protegrins, led to an assumption that hepcidin itself induces antimicrobial activity in vivo. Direct antimicrobial activity of hepcidin has to date been described only in in vitro conditions (2), while the in vivo hepcidin levels seem to be too low for this purpose. However, the fact is stressed that considering the weakened multiplication of microorganisms in an environment of a decreased iron concentration, the activity of hepcidin is a strongly constitutive element of the antimicrobial defensive system of our body (30).
Clinical use of determining the hepcidin concentration in inflammation
Alongside with describing the activity of hepcidin in inflammation the potential use of determining its level for diagnostic purposes was investigated. It is most likely that hepcidin concentration assay will be included in differential diagnosis of anemia and will decide about the necessity or contraindication to administer iron orally.
As opposed to iron deficiency anemia, when the hepcidin level is low, which allows a more effective absorption and release of iron reserve, the hepcidin level in chronic disease anemia is significantly increased (31). However, in iron deficiency anemia oral administration of iron is advisable, while in chronic disease anemia on the contrary, administering iron may be harmful (32), and certainly ineffective due to its inhibited absorption. At present, differentiating based on biochemical analyses is difficult and is not definitive, as in both types of anemia occurs a decreased iron concentration, and thus a the saturation of transferring also decreases. The concentration of ferritin is also not determining. Determining the hepcidin level as the only factor might in this case become decisive.
Determining hepcidin concentration does not belong to the diagnostic recommendations, which most likely results from the difficulties in a reliable determination of the level of this substance. The structure of the molecule initially prevented us from creating reliable immunoenzymatic assays (ELISA) that would guarantee differentiating the hepcidin isoforms and its species of origin. The concentration of hepcidin also depends on various factors, which include: sex, age, time of the day, as well as renal clearance, as it is mainly excreted in the urine (33). The work on creating laboratory norms for the specific clinical situations is underway.
Therapeutic perspectives on using substances that inhibit hepcidin activity in inflammation
The understanding of hepcidin activity has opened new perspectives for applying it for therapeutic purposes (tab. 3) (34). Administering hepcidin, its analogs or substances that participate in the activation of its transcription, might potentially be used in primary hemochromatosis, where occurs a decreased transcription of hepcidin or in ineffective erythropoiesis anemia, where the increase in hepcidin level is inhibited by tissue hypoxia and a high activity of agents released from bone marrow.
Tabela 3. Potential therapeutics which use the metabolic pathways of hepcidin.
Potential agonists and antagonists of hepcidin action
Stimulation of hepcidin activityInhibition of hepcidin activity(potential use in inflammation)
hepcidin
recombinant hepcidin
minihepcidin
bone morphogenetic
protein 6 (BMP6)
small peptides which
stimulate internalisation/
/degradation of ferroportin
removal of hepcidin by
hemodialysis
anti-hepcidin antibodies
anti-IL-6 and anti-r-IL-6 antibodies
anti-BMP6 antibodies
soluble hemojuvelin
molecule (sHJV)
erythropoietin or other
erythopoiesis stimulating agents
(EPO/ESA)
HIF inhibitors
The substances that weaken the activity of hepcidin might turn out to be useful in preventing the side effects of inflammation and might be administered in the treatment of chronic disease anemia (35). Moreover, they might also be applied in treating iron resistant syderopenic anemia, and in adenomas that produce excess hepcidin.
In experimental studies, antibodies were applied against the receptor for interleukin 6 (tocilizumab) in treating the effects of inflammation in anemia as a result of chronic arthritis in monkeys (36), anti-hepcidin antibody in chronic disease anemia in mice (37). In humans tocilizumab was applied in Castelman disease (38) and hemodialysis in order to get rid of excess hepcidin (39) with satisfactory results.

**This study was supported by CMKP. Grant number 501-1-1-20-33/10
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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

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