Pro-apoptotic and anti-apoptotic effects of transferrin and transferrin-derived glycans on hematopoietic cells and lymphocytes

Objective. The aim of this study was to test the hypothesis that transferri n (Tf) has anti-apoptotic properties and thereby exerts a cytoprotective ef fect against tissue damage induced by irradiation and other cytotoxic modal ities. Materials and Methods. This hypothesis was tested in several models, includ ing in vitro human short-term marrow cultures, subpopulations of marrow cel ls, particularly, CD56(+) natural killer cells (and natural killer cell lin es), and in vivo radioprotection of murine marrow cells. Reverse transcript ase polymerase chain reaction analysis was used for determination of cytoki ne mRNA, Results, Preincubation of human marrow with Tf protected cells (except for a CD56+ subpopulation) against cell death induced by gamma -irradiation, tu mor necrosis factor-alpha (TNF-alpha), and agonistic anti-Fas monoclonal an tibody, Deglycosylation of Tf abrogated this action of Tf; conversely, Tf-d erived glycans (Tf-Gly) (but not glycans isolated from other proteins) mimi cked the effects of the intact Tf molecule on apoptosis, Antibodies specifi c for the Tf receptor (CD71) did not block the effects of Tf or Tf-Gly on a poptosis, Determination of cytokine mRNA in the course of Fas-mediated apop tosis in the presence of Tf or Tf-Gly showed upregulation of mRNA for Fas l igand and TNF-alpha in CD56(+) and downregulation of these transcripts alon g with upregulation of mRNA for interleukin-10 in CD3(+) marrow cells. Unde r these conditions, a distinct increase in Fas-associated phosphatase-l mes sage was observed in CD3(+) cells that were protected by Tf or Tf-Gly again st apoptosis, The in vitro data mere confirmed in a murine in vivo model in which pretreatment of mice with Tf protected marrow cells against gamma -i rradiation-induced cell death. Conclusion. These data suggest a role for Tf and particularly Tf-Gly in the regulation of programmed cell death, apparently via alterations in cytokin e expression and provide a basis for additional studies on the use of Tf in cytoprotective protocols. (C) 2001 International Society for Experimental Hematology. published by Elsevier Science Inc.