Protection of human and murine hepatocytes against Fas-induced death by transferrin and iron.
Recent studies in a murine model show that transferrin (Tf) interferes with Fas-mediated hepatocyte death and liver failure by decreasing pro-apoptotic and increasing anti-apoptotic signals. We show here in vitro in murine and human hepatocyte cell lines and in vivo in mice that Fas-induced apoptosis is modulated by exogenous Tf and iron. The results obtained with iron-free Tf (ApoTf), iron-saturated Tf (FeTf), and the iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) in its iron-free and iron-saturated (FeSIH) forms indicate that apoptosis-modulating effects of Tf are not mediated by iron alone. Both the Tf molecule and iron affect multiple aspects of cell death, and the route of iron delivery to the cell may be critical for the final outcome of cellular Fas signaling. Survival of hepatocytes 'stressed' by Fas signals can be manipulated by Tf and iron and may be a target for prophylactic and therapeutic interventions.
Lesnikov
V A
VA
Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. vlesniko@fhcrc.org
Abbasi
N
N
Lesnikova
M P
MP
Lazaro
C A
CA
Campbell
J S
JS
Fausto
N
N
Deeg
H J
HJ
D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001483:Base Sequence; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014168:Transferrin / Q000378:metabolism / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000447:Aldehydes; D000911:Antibodies, Monoclonal; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494812:Bcl2l1 protein, mouse; C494815:Bid protein, mouse; D018076:DNA, Complementary; D006835:Hydrazones; D007502:Iron Chelating Agents; D012333:RNA, Messenger; D014168:Transferrin; D051020:bcl-X Protein; D019014:fas Receptor; C413684:salicylaldehyde isonicotinoyl hydrazone; D003609:Dactinomycin; D007501:Iron; C506433:CASP9 protein, human; D053453:Caspase 9