title: Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo.
abstract: BACKGROUND
  Increased levels of hepcidin, the master regulator of iron homeostasis, contribute to the diversion of iron underlying the anemia of chronic disease. Yet hepcidin levels are low in anemia of chronic disease with concomitant true iron deficiency. Here we clarify the different underlying pathways regulating hepcidin expression under these conditions in vivo.
  
  
  METHODS
  We used rat models of iron deficiency anemia, anemia of chronic disease and anemia of chronic disease with concomitant true iron deficiency and investigated upstream signaling pathways controlling hepcidin transcription in the liver. Protein and mRNA levels of iron metabolism genes and genes involved in SMAD1/5/8 and STAT3 signaling were determined by RT-PCR, Western blotting and immunohistochemistry.
  
  
  RESULTS
  SMAD1/5/8 phosphorylation and in parallel hepcidin mRNA expression were increased in anemia of chronic disease but significantly down-regulated in anemia of chronic disease with concomitant iron deficiency, either on the basis of phlebotomy or dietary iron restriction. Iron deficiency resulted in reduced bone morphogenetic protein-6 expression and impaired SMAD1/5/8 phosphorylation and trafficking, two key events for hepcidin transcription. Reduced SMAD1/5/8 activity in association with phlebotomy was paralleled by increased expression of the inhibitory factor, SMAD7, dietary iron restriction appeared to impair hepcidin transactivating SMAD pathways via reduction of membrane bound hemojuvelin expression.
  
  
  CONCLUSIONS
  This study evaluated hepcidin signaling pathways in anemia of chronic disease with/without concomitant iron deficiency in vivo. While iron deficiency in general decreased bone morphogenetic protein-6 expression, phlebotomy or dietary iron restriction inhibited inflammation driven SMAD1/5/8 mediated hepcidin formation by different pathways, indicating alternate hierarchic signaling networks as a function of the mode and kinetics of iron deficiency. Nonetheless, iron deficiency inducible regulatory pathways can reverse inflammation mediated stimulation of hepcidin expression.
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria. igor.theurl@i-med.ac.at
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.forename: Markus
authors.initials: M
authors.lastname: Seifert
authors.forename: Milan
authors.initials: M
authors.lastname: Theurl
authors.forename: Thomas
authors.initials: T
authors.lastname: Sonnweber
authors.forename: Hasan
authors.initials: H
authors.lastname: Kulaksiz
authors.forename: Guenter
authors.initials: G
authors.lastname: Weiss
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D064451:Hepcidins; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; C578703:Hamp protein, rat; D064451:Hepcidins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D051785:Smad Proteins; C494088:Stat3 protein, rat; D007501:Iron