title: Allogeneic transplantation, Fas signaling, and dysregulation of hepcidin.
abstract: Hepatic iron overload is common in patients undergoing hematopoietic cell transplantation. We showed previously in a murine model that transplantation of allogeneic T cells induced iron deposition and down-regulation of hepcidin (Hamp) in hepatocytes. We hypothesized that hepatic injury was related to disrupted iron homeostasis triggered by the interaction of Fas-ligand, expressed on activated T cells, with Fas on hepatocytes. In the current study, we determined the effects of modified expression of the Flice inhibitory protein (FLIP long [FLIPL]), which interferes with Fas signaling, on the impact of Fas-initiated signals on the expression of IL-6 and Stat3 and their downstream target, Hamp. To exclude a possible contribution by other pathways, we used agonistic anti-Fas antibodies (rather than allogeneic T cells) to trigger Fas signaling. Inhibition of FLIPL by RNA interference resulted, as expected, not only in enhanced hepatocyte apoptosis in response to Fas signals, but also in decreased levels of IL-6, Stat3, and Hamp. In contrast, overexpression of FLIPL protected hepatocytes against agonistic anti-Fas antibody-mediated apoptosis and increased the levels of IL-6 and Stat3, thereby maintaining the expression of Hamp in an NF-κB-dependent fashion. In vivo overexpression of FLIPL in the liver via hydrodynamic transfection, similarly, interfered with Fas-initiated apoptosis and prevented down-regulation of IL-6, Stat3, and Hamp. These data indicate that Fas-dependent signals alter the regulation of iron homeostasis and suggest that signals initiated by Fas may contribute to peritransplantation iron accumulation.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Ekapun
authors.initials: E
authors.lastname: Karoopongse
authors.forename: A Mario
authors.initials: AM
authors.lastname: Marcondes
authors.forename: Kayoung
authors.initials: K
authors.lastname: Lee
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.forename: Carol H
authors.initials: CH
authors.lastname: Miao
authors.forename: Grant D
authors.initials: GD
authors.lastname: Trobridge
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D064451:Hepcidins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D019190:Iron Overload / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D014162:Transfection; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D064451:Hepcidins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D019014:fas Receptor
keywords: Apoptosis; FLIP Long; Hepcidin; Iron