MODULATION OF IRON-METABOLISM IN MONOCYTIC THP-1 CELLS AND CULTURED HUMAN MONOCYTES BY THE ACUTE-PHASE PROTEIN ALPHA-1-ANTITRYPSIN

The reticuloendothelial (RE) system plays an important role in the cha nges in iron metabolism associated with the anemia of chronic disease (ACD). We previously reported that the acute-phase protein alpha 1-ant itrypsin (alpha 1-AT) reduced growth and proliferation in cells of the erythroid cell system by interfering with transferrin (Tf)-mediated i ron uptake. The regulation of iron metabolism in cells of the RE syste m is distinctly different from that in other cell systems; moreover, m onocytes and macrophages play an essential part in the regulation of t he production and clearance of alpha 1-AT. In the present study we exa mined the effect of alpha 1-AT on cells of the monocyte-macrophage lin eage. alpha 1-AT completely inhibited the binding of Tf to its recepto r (TfR) on THP-1 human myelomonocytic cells and cultured human monocyt es. Results of equilibrium saturation and kinetic studies indicated th at this inhibition was Competitive. No other acute-phase protein demon strated the same inhibitory potency. Furthermore, alpha 1-AT almost co mpletely prevented internalization of the Tf-TfR complex in a dose-dep endent manner. Interestingly, and in sharp contrast to the results of our studies with erythroid cells, this inhibition did not reduce the g rowth and proliferation of THP-1 cells. Furthermore, alpha 1-AT signif icantly increased the concentration of intracellular ferritin in THP-1 cells and monocytes, whereas the number of TfR remained unchanged. Be cause alpha 1-AT showed no enhancing effect on ferritin transcription and translation, we believe that an as-yet unidentified posttranslatio nal mechanism may be responsible for this phenomenon. In addition, our results indicate that the increase in ferritin concentration caused b y alpha 1-AT is mediated independently of iron supply, as has previous ly been shown for several proinflammatory cytokines. These data provid e further evidence that alpha 1-AT is a mediator of the alterations in iron metabolism characteristic of ACD.