Abstract

Hepcidin is a 25-amino-acid peptide synthesized predominantly in hepatocytes, which plays an essential role in the regulation of systemic iron homeostasis. As a result of inflammation, hepcidin binds to ferroportin resulting in its internalization and degradation in enterocytes and macrophages. Thus iron is trapped in both enterocytes and macrophages, leading to functional hypoferremia. In iron deficiency or enhanced erythropoiesis, hepcidin expression is reduced. That fact results in increase of iron absorption and releasing iron storage from macrophages. The discovery of the biological properties of hepcidin clarified the relationship between iron homeostasis, immune response, and anaemia of chronic disease. Anaemia is the most common extra intestinal manifestation of inflammatory bowel disease. Anaemia significantly reduces the quality-of-life among patients and can lead to a number of serious complications, even life-threatening. The main types of anaemia in inflammatory bowel diseases are iron deficiency anaemia and anaemia of chronic disease. These two types of anaemia coexist commonly. The key issue is differentiation these types of anaemia to implement a proper management. Commonly used parameters as iron concentration, ferritin and transferrin, are rather unreliable indices for the evaluation of anaemia in inflammatory bowel diseases. In recent studies the important role of hepcidin as a potential alternative marker of anemia and iron status has been shown. Moreover, there are data that antihepcidin treatment may be an effective treatment of anaemia of chronic disease in inflammatory bowel disease. This paper presents hepcidin structure, mechanism of action and regulation, and highlights hepcidin function in anaemia in inflammatory bowel disease.

References

• 1. Abboud S., Haile D.J.: A novel mammalian iron-regulated proteininvolved in intracellular iron metabolism. J. Biol. Chem., 2000;275: 19906-19912
  Google Scholar
• 2. Andrews N.C.: Forging a field: the golden age of iron biology.Blood, 2008; 112: 219-230
  Google Scholar
• 3. Andriopoulous B.Jr., Corradini E., Xia Y., Faasse S.A., Chen S., GrgurevicL., Knutson M.D., Pietrangelo A., Vukicevic S., Lin H.Y., BabittJ.L.: BMP6 is a key endogenous regulator of hepcidin expression andiron metabolism. Nat. Genet., 2009; 41: 482-487
  Google Scholar
• 4. Arnold J., Sangwaiya A., Bhatkal B., Geoghegan F., Busbridge M.:Hepcidin and inflammatory bowel disease: dual role in host defenceand iron homeostasis. Eur. J. Gastroenterol. Hepatol., 2009;21: 425-429
  Google Scholar
• 5. Atanasiu V., Manolescu B., Stoian I.: Hepcidin – central regulatorof iron metabolism. Eur. J. Haematol., 2007; 78: 1-10
  Google Scholar
• 6. Babitt J.L., Huang F.W., Wrighting D.M., Xia Y., Sidis Y., SamadT.A., Campagna J.A., Chung R.T., Schneyer A.L., Woolf C.J., AndrewsN.C., Lin H.Y.: Bone morphogenetic protein signaling by hemojuvelinregulates hepcidin expression. Nat. Genet., 2006; 38: 531-539
  Google Scholar
• 7. Babitt J.L., Huang F.W., Xia Y., Sidis Y., Andrews N.C., Lin H.Y.: Modulationof bone morphogenetic protein signaling in vivo regulatessystemic iron balance. J. Clin. Invest., 2007; 117: 1933-1939
  Google Scholar
• 8. Bacchetta J., Zaritsky J.J., Sea J.L., Chun R.F., Lisse T.S., Zavala K.,Nayak A., Wesseling-Perry K., Westerman M., Hollis B.W., Salusky I.B.,Hewison M.: Suppression of iron-regulatory hepcidin by vitamin D.J. Am. Soc. Nephrol., 2014; 25: 564-572
  Google Scholar
• 9. Basseri R.J., Nemeth E., Vassilaki M.E., Basseri B., Enayati P., ShayeO., Bourikas L.A., Ganz T., Papadakis K.A.: Hepcidin is a key mediatorof anemia of inflammation in Crohn’s disease. J. Crohns Colitis,2013; 7: e286-e291
  Google Scholar
• 10. Bergamaschi G., Di Sabatino A., Albertini R., Costanzo F., GuerciM., Masotti M., Pasini A., Massari A., Campostrini N., CorbellaM.,Girelli D., Corazza G.R.: Serum hepcidin in inflammatory boweldiseases: biological and clinical significance. Inflamm. Bowel Dis.,2013; 19: 2166-2172
  Google Scholar
• 11. Bregman D.B., Morris D., Koch T.A., He A.,Goodnough L.T.: Hepcidinlevels predict nonresponsiveness to oral iron therapy in patientswith iron deficiency. Am. J. Hematol., 2013; 88: 97-101
  Google Scholar
• 12. Dallalio G., Law E., Means R.T. Jr.: Hepcidin inhibits in vitro erythroidcolony formation at reduced erytropoietin concentration.Blood, 2006; 107: 2702-2704
  Google Scholar
• 13. De Domenico I., Ward D.M., Langelier C., Vaughn M.B., NemethE., Sundquist W.I., Ganz T., Musci G., Kaplan J.: The molecular mechanismof hepcidin-mediated ferroportin down-regulation. Mol.Biol. Cell, 2007; 18: 2569-2578
  Google Scholar
• 14. Donovan A., Brownlie A., Zhou Y., Shepard J., Pratt S.J., MoynihanJ., Paw B.H., Drejer A., Barut B., Zapata A., Law T.C., BrugnaraC., Lux S.E., Pinkus G.S., Pinkus J.L. i wsp.: Positional cloning of zebrafishferroportin1 identifies a conserved vertebrate iron exporter.Nature, 2000; 403: 776-781
  Google Scholar
• 15. Evstatiev R., Gasche C.: Iron sensing and signaling. Gut, 2012;61: 933-952
  Google Scholar
• 16. Galy B., Ferring-Appel D., Kaden S., Gröne H.J., Hentze M.W.:Iron regulatory proteins are essential for intestinal function andcontrol key iron absorption molecules in the duodenum. Cell Metab.,2008; 7: 79-85
  Google Scholar
• 17. Ganz T.: Hepcidin, a key regulator of iron metabolism and mediatorof anemia of inflammation. Blood, 2003; 102: 783-788
  Google Scholar
• 18. Ganz T.: Iron homeostasis: fitting the puzzle pieces together.Cell Metab., 2008; 7: 288-290
  Google Scholar
• 19. Ganz T., Nemeth E.: Iron imports. IV. Hepcidin and regulation ofbody iron metabolism. Am. J. Physiol. Gastrointest. Liver Physiol.,2006; 290: G199-G203
  Google Scholar
• 20. Ganz T., Olbina G., Girelli D., Nemeth E., Westerman M.: Immunoassayfor human serum hepcidin. Blood, 2008; 112: 4292-4297
  Google Scholar
• 21. Gasche C., Lomer M.C., Cavill I., Weiss G.: Iron, anaemia, and inflammatorybowel diseases. Gut, 2004; 53: 1190-1197
  Google Scholar
• 22. Gomollón F., Gisbert J.P.: Anemia and inflammatory bowel diseases.World J. Gastroenterol., 2009; 15: 4659-4665
  Google Scholar
• 23. Huang H., Constante M., Layoun A., Santos M.M.: Contributionof STAT3 and STAT4 pathways to the regulation of hepcidin by opposingstimuli. Blood, 2009; 113: 3593-3599
  Google Scholar
• 24. Kemna E., Tjalsma H., Laarakkers C., Nemeth E., Willems H.,Swinkels D.: Novel urine hepcidin assay by mass spectrometry. Blood,2005; 106: 3268-3270
  Google Scholar
• 25. Krause A., Neitz S., Mägert H.J., Schulz A., Forssmann W.G.,Schulz-Knappe P., Adermann K.: LEAP-1, a novel highly disulfide–bonded human peptide, exhibits antimicrobial activity. FEBS Lett.,2000; 480: 147-150
  Google Scholar
• 26. Krzesiek E., Flis A., Iwańczak B.: Ocena występowania niedokrwistościwe wrzodziejącym zapaleniu jelita grubego u dzieci. Pol. Merkur.Lekarski, 2012; 33: 138-142
  Google Scholar
• 27. Lee D.H., Zhou L.J., Zhou Z., Xie J.X., Jung J.U., Liu Y., Xi C.X., Mei L.,Xiong W.C.: Neogenin inhibits HJV secretion and regulates BMP-inducedhepcidin expression and iron homeostasis. Blood, 2010; 115: 3136-3145
  Google Scholar
• 28. Lee P.: Role of matriptase-2 (TMPRSS6) in iron metabolism. ActaHaematol., 2009; 122: 87-96
  Google Scholar
• 29. Lee P., Peng H., Gelbart T., Wang L., Beutler E.: Regulation of hepcidintranscription by interleukin-1 and interleukin-6. Proc. Natl. Acad.Sci. USA, 2005; 102: 1906-1910
  Google Scholar
• 30. Lipiński P., Starzyński R.R.: Regulacja ogólnoustrojowej homeostazyżelaza przez hepcydynę. Postępy Hig. Med. Dośw., 2004; 58: 65-73
  Google Scholar
• 31. Lymboussaki A., Pignatti E., Montosi G., Garuti C., Haile D.J., PietrangeloA.: The role of the iron responsive element in the control offerroportin1/IREG1/MTP1 gene expression. J. Hepatol., 2003; 39: 710-715
  Google Scholar
• 32. Macdougall I.C., Malyszko J., Hider R.C., Bansal S.S.: Current statusof the measurement of blood hepcidin levels in chronic kidney disease.Clin. J. Am. Soc. Nephrol., 2010; 5: 1681-1689
  Google Scholar
• 33. Malyszko J.: Hepcidin assays: ironing out some details. Clin. J. Am.Soc. Nephrol., 2009; 4: 1015-1016
  Google Scholar
• 34. Nemeth E., Ganz T.: The role of hepcidin in iron metabolism. ActaHaematol., 2009; 122: 78-86
  Google Scholar
• 35. Nemeth E., Preza G.C., Jung C.L., Kaplan J., Waring A.J., Ganz T.: TheN-terminus of hepcidin is essential for its interaction with ferroportin:structure-function study. Blood, 2006; 107: 328-333
  Google Scholar
• 36. Nemeth E., Tuttle M.S., Powelson J., Vaughn M.B., Donovan A., WardD.M., Ganz T., Kaplan J.: Hepcidin regulates cellular iron efflux by bindingto ferroportin and inducing its internalization. Science, 2004; 306:2090-2093
  Google Scholar
• 37. Nemeth E., Valore E.V., Territo M., Schiller G., Lichtenstein A., GanzT.: Hepcidin, a putative mediator of anemia of inflammation, is a typeII acute-phase protein. Blood, 2003; 101: 2461-2463
  Google Scholar
• 38. Nicolas G., Bennoun M., Devaux I., Beaumont C., Grandchamp B.,Kahn A., Vaulont S.: Lack of hepcidin gene expression and severe tissueiron overload in upstream stimulatory factor 2 (USF2) knockout mice.Proc. Natl. Acad. Sci. USA, 2001; 98: 8780-8785
  Google Scholar
• 39. Nicolas G., Bennoun M., Porteu A., Mativet S., Beaumont C., GrandchampB., Sirito M., Sawadogo M., Kahn A., Vaulont S.: Severe iron deficiencyanemia in transgenic mice expressing liver hepcidin. Proc. Natl.Acad. Sci. USA, 2002; 99: 4596-4601
  Google Scholar
• 40. Niederkofler V., Salie R., Arber S.: Hemojuvelin is essential for dietaryiron sensing, and its mutation leads to severe iron overload. J. Clin.Invest., 2005; 115: 2180-2186
  Google Scholar
• 41. Oustamanolakis P., Koutroubakis I.E., Kouroumalis E.A.: Diagnosinganemia in inflammatory bowel disease: beyond the established markers.J. Crohns Colitis, 2011; 5: 381-391
  Google Scholar
• 42. Oustamanolakis P., Koutroubakis I.E., Messaritakis I., MalliarakiN., Sfiridaki A., Kouroumalis E.A.: Serum hepcidin and prohepcidinconcentrations in inflammatory bowel disease. Eur. J. Gastroenterol.Hepatol., 2011; 23: 262-268
  Google Scholar
• 43. Park C.H., Valore E.V., Waring A.J., Ganz T.: Hepcidin, a urinary antimicrobialpeptide synthesized in the liver. J. Biol. Chem., 2001; 276:7806-7810
  Google Scholar
• 44. Peslova G., Petrak J., Kuzelova K., Hrdy I., Halada P., Kuchel P.W.,Soe-Lin S., Ponka P., Sutak R., Becker E., Huang M.L., Rahmanto Y.S.,Richardson D.R., Vyoral D.: Hepcidin, the hormone of iron metabolism,is bound specifically to α-2-macroglobulin in blood. Blood,2009; 113: 6225-6236
  Google Scholar
• 45. Peyssonnaux C., Zinkernagel A.S., Schuepbach R.A., Rankin E., VaulontS., Haase V.H., Nizet V., Johnson R.S.: Regulation of iron homeostasisby the hypoxia-inducible transcription factors (HIFs). J. Clin. Invest.,2007; 117: 1926-1932
  Google Scholar
• 46. Pigeon C., Ilyin G., Courselaud B., Leroyer P., Turlin B., Brissot P.,Loréal O.: A new mouse liver-specific gene, encoding a protein homologousto human antimicrobial peptide hepcidin, is overexpressed duringiron overload. J. Biol. Chem., 2001; 276: 7811-7819
  Google Scholar
• 47. Pytrus T., Flis A., Iwańczak F., Iwańczak B.: Częstość występowanianiedokrwistości u dzieci z nowo rozpoznaną chorobą Leśniowskiego–Crohna. Pol. Merkur. Lekarski, 2013; 34: 263-268
  Google Scholar
• 48. Radwan P., Radwan-Kwiatek K., Skrzydło-Radomańska B., RydzewskaG.: Niedokrwistość w nieswoistych zapaleniach jelit – etiopatogeneza,rozpoznawanie i leczenie. Przegl. Gastroenterol., 2010; 5: 315-320
  Google Scholar
• 49. Reinisch W., Staun M., Bhandari S., Munoz M.: State of the iron: howto diagnose and efficiently treat iron deficiency anemia in inflammatorybowel disease. J. Crohns Colitis, 2013; 7: 429-440
  Google Scholar
• 50. Rivera S., Nemeth E., Gabayan V., Lopez M.A., Farshidi D., Ganz T.:Synthetic hepcidin causes rapid dose-dependent hypoferremia andis concentrated in ferroportin-containing organs. Blood, 2005; 106:2196-2199
  Google Scholar
• 51. Sasu B.J., Cooke K.S., Arvedson T.L., Plewa C., Ellison A.R., Sheng J.,Winters A., Juan T., Li H., Begley C.G., Molineux G.: Antihepcidin antibodytreatment modulates iron metabolism and its effective in a mousemodel of inflammation-induced anemia. Blood, 2010; 115: 3616-3624
  Google Scholar
• 52. Silvestri L., Pagani A., Camaschella C.: Furin-mediated release ofsoluble hemojuvelin: a new link between hypoxia and iron homeostasis.Blood, 2008; 111: 924-931
  Google Scholar
• 53. Sokołowska E., Klimek J.: Hepcydyna – hormon uczestniczący w regulacjimetabolizmu żelaza w organizmie. Postępy Biol. Kom., 2007;34: 15-30
  Google Scholar
• 54. Tanno T., Bhanu N.V., Oneal P.A., Goh S.H., Staker P., Lee Y.T., MoroneyJ.W., Reed C.H., Luban N.L., Wang R.H., Eling T.E., Childs R., GanzT., Leitman S.F., Fucharoen S., Miller J.L.: High levels of GDF15 in thalassemiasuppress expression of the iron regulatory protein hepcidin.Nat. Med., 2007; 13: 1096-1101
  Google Scholar
• 55. Tanno T., Porayette P., Sripichai O., Noh S.J., Byrnes C., BhupatirajuA., Lee Y.T., Goodnough J.B., Harandi O., Ganz T., Paulson R.F., Miller J.L.:Identification of TWSG1 as a second novel erythroid regulator of hepcidinexpression in murine and human cells. Blood, 2009; 114: 181-186
  Google Scholar
• 56. Van Assche G., Dignass A., Bokemeyer B., Danese S., Gionchetti P.,Moser G., Beaugerie L., Gomollón F., Häuser W., Herrlinger K., OldenburgB., Panes J., Portela F., Rogler G., Stein J. i wsp.: Second Europeanevidence-based consensus on the diagnosis and management of ulcerativecolitis Part 3: Special situations. J. Crohns Colitis, 2013; 7: 1-33
  Google Scholar
• 57. Wang L., Trebicka E., Fu Y., Ellenbogen S., Hong C.C., Babitt J.L., LinH.Y., Cherayil B.J.: The bone morphogenetic protein-hepcidin axis asa therapeutic target in inflammatory bowel disease. Inflamm. BowelDis., 2012; 18: 112-119
  Google Scholar
• 58. Wang R.H., Li C., Xu X., Zheng Y., Xiao C., Zerfas P., Cooperman S.,Eckhaus M., Rouault T., Mishra L., Deng C.X.: A role of SMAD4 in ironmetabolism through the positive regulation of hepcidin expression.Cell Metab., 2005; 2: 399-409
  Google Scholar
• 59. Zarychanski R., Houston D.S.: Anemia of chronic disease: a harmfuldisorder or an adaptive, beneficial response? CMAJ, 2008; 179: 333-337
  Google Scholar
• 60. Zhang D.L., Hughes R.M., Ollivierre-Wilson H., Ghosh M.C., RouaultT.A.: A ferroportin transcript that lacks an iron-responsive elementenables duodenal and erythroid precursor cells to evade translationalrepression. Cell Metab., 2009; 9: 461-473
  Google Scholar

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