Divergent effects of alpha 1-antitrypsin on the regulation of iron metabolism in human erythroleukaemic (K562) and myelomonocytic (THP-1) cells.
The acute-phase protein alpha 1-antitrypsin (alpha 1-AT) has been shown to inhibit the binding of transferrin to its cell-surface receptor. Here we demonstrate that in human erythroleukaemic cells (K562) alpha 1-AT enhances the binding affinity of iron-regulatory protein (IRP), the central regulator of cellular iron metabolism, to iron-responsive elements. Activation of IRP by alpha 1-AT is associated with a marked increase in transferrin receptor (trf-rec) mRNA levels in K562 and enhanced cell-surface expression of transferrin-binding sites, whereas ferritin production is decreased, although ferritin mRNA levels remain unchanged. In agreement with the well-established mechanism of cellular iron regulation, alpha 1-AT seems to modulate trf-rec and ferritin expression primarily post-transcriptionally/translationally by influencing IRP activity. In contrast, alpha 1-AT produces only minor changes in IRP activity, and subsequently in trf-rec expression and ferritin synthesis in THP-1 cells. Moreover the effects of alpha 1-AT on iron homeostasis in K562 cannot be overcome by the addition of iron salts, whereas concomitant treatment of THP-1 with iron and alpha 1-AT results in the same metabolic changes as the addition of iron alone. Because alpha 1-AT blocks transferrin binding on K562 as well as on THP-1 cells, it is suggested, on the basis of the results presented here, (1) that erythroid and monocytic cells might differ in their dependence on transferrin-mediated iron supply and (2) that THP-1 might be able to acquire iron by a transferrin-independent iron uptake system. alpha 1-AT might therefore be involved in the diversion of iron traffic between various cellular compartments under inflammatory conditions.
Weiss
G
G
Department of Internal Medicine, University Hospital, Innsbruck, Austria.
Graziadel
I
I
Urbanek
M
M
Grünewald
K
K
Vogel
W
W
D002460:Cell Line; D003676:Deferoxamine / Q000494:pharmacology*; D005293:Ferritins / Q000096:biosynthesis*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute; D015479:Leukemia, Myelomonocytic, Acute; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011990:Receptors, Transferrin; D000515:alpha 1-Antitrypsin; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine