title: Ferritin--a mediator of apoptosis?
abstract: Previously we have demonstrated an apoptosis inducing activity for a rat hepatocyte conditioned medium (CM) presumably mediated by acidic isoferritins. Here, we present support for this assumption since isoferritins purified from different rat hepatocyte CM significantly enhanced the frequency of apoptotic cells in primary rat hepatocytes, an effect completely inhibited by a neutralizing anti-H-ferritin antibody. The apoptosis induction appears to be related to a 43 kDa ferritin subunit contained in the isoferritins released from primary hepatocytes, presumably representing a ferritin heavy/light chain heterodimer. In addition, these isoferritins immunologically crossreact with antibodies raised against placental isoferritin p43-PLF (which also contains a 43 kDa ferritin subunit) and melanoma-derived H-chain ferritin, representing ferritin isoforms which reveal immunomodulatory properties. Furthermore, p53 and FasL are upregulated upon isoferritin treatment in a time dependent mode, and apoptosis induction can be suppressed by neutralizing anti-FasL antibodies. Proapoptotic Bid is upregulated too and translocated into mitochondria in primary hepatocytes exposed to the isoferritins purified from the CM. Finally, epidermal growth factor (EGF) and dexamethasone (DEX), which counteract proapoptotic mitochondrial signalling, almost completely abolished the proapoptotic effect of the hepatocyte derived isoferritins. In conclusion, our findings demonstrate that acidic isoferritins with homology to immunomodulatory ferritin isoforms (p43-PLF, melanoma-derived-H-chain ferritin) are released from hepatocytes in vitro, and are able to stimulate upregulation of p53 and mediate apoptosis involving Fas (CD95) signalling as well as addressing the intrinsic mitochondrial proapoptotic pathway.
authors.affiliation: Department of Cell Biology, University of Salzburg, Salzburg, Austria. nikolaus.bresgen@sbg.ac.at
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Bresgen
authors.forename: Ingo
authors.initials: I
authors.lastname: Ohlenschläger
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fiedler
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wacht
authors.forename: Susanne
authors.initials: S
authors.lastname: Zach
authors.forename: Bettina
authors.initials: B
authors.lastname: Dunkelmann
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kuffner
authors.forename: Friedrich
authors.initials: F
authors.lastname: Lottspeich
authors.forename: Peter M
authors.initials: PM
authors.lastname: Eckl
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D017077:Culture Media, Conditioned; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D005293:Ferritins