Prevention of Fas-mediated hepatic failure by transferrin.
Recent studies in lymphohemopoietic cells show that transferrin (Tf), a pivotal component of iron transport and metabolism, also exerts cytoprotective functions. We show here in a murine model that Tf interferes with Fas-mediated hepatocyte death and liver failure. The mechanism involves the downregulation of apoptosis via BID, cytochrome c, caspase-3 and caspase-9, and upregulation of antiapoptotic signals via Bcl-xL. The results obtained with iron-saturated Tf, Apo-Tf and the iron-chelator salicylaldehyde isonicotinoyl hydrazone indicate that the observed antiapoptotic effect of Tf was not mediated by iron alone. In conclusion, the data suggest that Tf has broader functions than previously recognized and may serve as a cytoprotective agent.
Lesnikov
Vladimir A
VA
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. vlesniko@fhcrc.org
Lesnikova
Marina P
MP
Shulman
Howard M
HM
Wilson
Heather-Marie
HM
Hockenbery
David M
DM
Kocher
Markus
M
Pierpaoli
Walter
W
Deeg
H Joachim
HJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D017093:Liver Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014168:Transferrin / Q000494:pharmacology*; D051020:bcl-X Protein; D019014:fas Receptor / Q000502:physiology*
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; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014168:Transferrin; D051020:bcl-X Protein; D019014:fas Receptor; D045304:Cytochromes c; D007501:Iron; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases