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: Xiang Li, Feng Xu, Ekapun Karoopongse, A Mario Marcondes, Kayoung Lee, Kris V Kowdley, Carol H Miao, Grant D Trobridge, Jean S Campbell, H Joachim Deeg
• Journal: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (Biol Blood Marrow Transplant) Vol. 19 Issue 8 Pg. 1210-9 (Aug 2013) ISSN: 1523-6536 [Electronic] United States
• PMID: 23707854 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Fas Ligand Protein
• Hepcidins
• Interleukin-6
• STAT3 Transcription Factor
• fas Receptor

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Apoptosis (physiology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (antagonists & inhibitors, biosynthesis, metabolism)
• Cell Line, Tumor
• Fas Ligand Protein (metabolism)
• Female
• Hepatocytes (immunology, metabolism)
• Hepcidins (biosynthesis, genetics, metabolism)
• Humans
• Interleukin-6 (biosynthesis, genetics)
• Iron Overload (etiology, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• STAT3 Transcription Factor (biosynthesis, genetics)
• Signal Transduction
• T-Lymphocytes (immunology, metabolism, transplantation)
• Transfection
• Transplantation, Homologous
• Treatment Outcome
• fas Receptor (immunology, metabolism)