title: Tumor necrosis factor-alpha and interleukin 1-alpha regulate transferrin receptor in human diploid fibroblasts. Relationship to the induction of ferritin heavy chain.
abstract: We have studied transferrin receptor expression in MRC5 human fibroblasts in response to tumor necrosis factor-alpha (TNF, cachectin) or interleukin 1-alpha (IL-1). Treatment of exponentially growing MRC5 cells with these cytokines led to a 3-4-fold increase in transferrin receptor mRNA and a coordinate increase in transferrin receptor protein by 24 h. Under these conditions, stimulation of [3H]thymidine incorporation was minimal, suggesting that the induction of transferrin receptor by TNF and IL-1 is mediated by a growth-independent regulatory mechanism. A study of the time course of this response showed that cytokine-mediated increases in transferrin receptor mRNA and protein proceeded after a lag of 12-24 h. A simultaneous analysis of the effects of TNF and IL-1 on ferritin in MRC5 cells was also performed. Ferritin L mRNA levels were unchanged. However, induction of ferritin H mRNA was seen within 4 h, preceding the induction of the transferrin receptor. The synthesis of ferritin H (but not ferritin L) protein peaked at 8 h after TNF or IL-1 treatment, followed by a rapid decrease in both ferritin H and L protein synthesis. As ferritin H synthesis declined, levels of transferrin receptor protein increased, reaching a maximum by 24 h. These results suggest that the cytokine-dependent induction of ferritin H and subsequent increase in the transferrin receptor are related and possibly interdependent events. This study demonstrates that the complex role of TNF and IL-1 in iron homeostasis includes modulation of the transferrin receptor.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, California 94305.
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuji
authors.forename: L L
authors.initials: LL
authors.lastname: Miller
authors.forename: S C
authors.initials: SC
authors.lastname: Miller
authors.forename: S V
authors.initials: SV
authors.lastname: Torti
authors.forename: F M
authors.initials: FM
authors.lastname: Torti
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004171:Diploidy; D005293:Ferritins / Q000096:biosynthesis*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D046911:Macromolecular Substances; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D011990:Receptors, Transferrin / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D007375:Interleukin-1; D046911:Macromolecular Substances; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D005293:Ferritins