Allogeneic Transplantations, Fas Signaling, and Dysregulation of Hepcidin.

Publication Type:

Journal Article


Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Volume 19, Issue 8, p.1210-9 (2013)


2013, Center-Authored Paper, Clinical Research Division, Experimental Histopathology Core Facility, Flow Cytometry Core Facility, June 2013, Translational Bioimaging Center Core Facility


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, 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.