Modulation of iron metabolism in monocytic THP-1 cells and cultured human monocytes by the acute-phase protein alpha1-antitrypsin.
The reticuloendothelial (RE) system plays an important role in the changes in iron metabolism associated with the anemia of chronic disease (ACD). We previously reported that the acute-phase protein alpha1-antitrypsin (alpha1-AT) reduced growth and proliferation in cells of the erythroid cell system by interfering with transferrin (Tf)-mediated iron uptake. The regulation of iron metabolism in cells of the RE system is distinctly different from that in other cell systems; moreover, monocytes and macrophages play an essential part in the regulation of the production and clearance of alpha1-AT. In the present study we examined the effect of alpha1-AT on cells of the monocyte-macrophage lineage. Alpha1-AT completely inhibited the binding of Tf to its receptor (TfR) on THP-1 human myelomonocytic cells and cultured human monocytes. Results of equilibrium saturation and kinetic studies indicated that this inhibition was competitive. No other acute-phase protein demonstrated the same inhibitory potency. Furthermore, alpha1-AT almost completely prevented internalization of the Tf-TfR complex in a dose-dependent manner. Interestingly, and in sharp contrast to the results of our studies with erythroid cells, this inhibition did not reduce the growth and proliferation of THP-1 cells. Furthermore, alpha1-AT significantly increased the concentration of intracellular ferritin in THP-1 cells and monocytes, whereas the number of TfR remained unchanged. Because alpha1-AT showed no enhancing effect on ferritin transcription and translation, we believe that an as-yet unidentified posttranslational mechanism may be responsible for this phenomenon. In addition, our results indicate that the increase in ferritin concentration caused by alpha1-AT is mediated independently of iron supply, as has previously been shown for several proinflammatory cytokines. These data provide further evidence that alpha1-AT is a mediator of the alterations in iron metabolism characteristic of ACD.
Graziadei
I
I
Department of Internal Medicine, University of Innsbruck, Austria.
Weiss
G
G
Egger
C
C
Niederwieser
D
D
Patsch
J R
JR
Vogel
W
W
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005293:Ferritins / Q000096:biosynthesis; D006801:Humans; D007457:Iodine Radioisotopes; D007501:Iron / Q000097:blood* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000096:biosynthesis; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
D007457:Iodine Radioisotopes; D011990:Receptors, Transferrin; D000515:alpha 1-Antitrypsin; D004247:DNA; D005293:Ferritins; D007501:Iron