title: GDF15-mediated upregulation of ferroportin plays a key role in the development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis.
abstract: BACKGROUND
  Growth differentiation factor 15 (GDF15), a divergent TGFβ superfamily, has recently been implicated in the modulation of iron homeostasis, acting as an upstream negative regulator of hepcidin, the key iron regulatory hormone produced primarily by hepatocytes. However, little is known about possible roles that GDF15 might play in the regulation of iron homeostasis and development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis (HLH).
  
  
  METHODS
  We compared serum GDF15 level and mRNA expressions of GDF15 and key molecules of iron metabolism, and made correlations between their expressions in children with HLH and control children.
  
  
  RESULTS
  Serum GDF15 level was remarkably higher in HLH group than that in controls, with median serum concentration of 1,700 and 260 pg/ml, respectively (P < 0.001). In addition, GDF15 mRNA was significantly upregulated but independent of hypoxia-inducible factor-mediated oxygen signaling pathway. More importantly, GDF15 induction was positively correlated to upregulation of ferroportin, the only cellular iron exporter, and to upregulation of ferritin heavy chain.
  
  
  CONCLUSIONS
  Our study suggests that GDF15 induction helps suppress further activation of macrophages in stressful physiologic states as HLH, and is intimately implicated in the development of hyperferritinemia by modulating the hepcidin-ferroportin axis, resulting in enhanced ferroportin-mediated iron efflux.
authors: Hematology and Oncology Unit, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.
authors: Jian-Rong
authors: JR
authors: Wu
authors: Li-Xing
authors: LX
authors: Yuan
authors: Zhi-Gui
authors: ZG
authors: Ma
authors: Xiao-Xi
authors: XX
authors: Chen
authors: Ling
authors: L
authors: Gu
authors: Ju
authors: J
authors: Gao
mesh_terms: D000293:Adolescent; D027682:Cation Transport Proteins / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007501:Iron / Q000378:metabolism*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000378:metabolism*; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D055436:Growth Differentiation Factor 15; D000098742:Ferroportin; D007501:Iron