The acute-phase protein alpha 1-antitrypsin inhibits growth and proliferation of human early erythroid progenitor cells (burst-forming units-erythroid) and of human erythroleukemic cells (K562) in vitro by interfering with transferrin iron uptake.

We have previously shown that the hepatic acute-phase protein alpha 1-antitrypsin (alpha 1-AT) inhibits transferrin (tf) binding to its receptor (tfR) of human placental membranes. To evaluate the possibility that this interaction can explain the pathophysiology of the changes in iron metabolism in the course of chronic disease, subsequently leading to anemia in chronic disease (ACD), we examined the effect of alpha 1-AT on cells of the erythroid cell line. alpha 1-AT completely prevented tf binding to tfR on K562 human erythroleukemic cells and on reticulocytes. This inhibitory potency was dose-dependent and competitive, as proved in equilibrium saturation and kinetic studies. The cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha showed no such effect. Internalization of the tf-tfR complex was inhibited with alpha 1-AT in a dose-dependent manner. Furthermore, alpha 1-AT profoundly reduced the growth of K562 cells as well as their proliferation, albeit to a lesser degree. Growth of early erythroid progenitor cells (burst-forming units-erythroid) was significantly suppressed by alpha 1-AT, but no effect on the growth of late erythroid progenitor cells (colony-forming units-erythroid) was detected. These inhibitions of alpha 1-AT were seen in high physiologic concentrations attained in the course of acute-phase situations. These data show that alpha 1-AT might be a mediator of the changes in iron metabolism that are characteristic of clinical findings in the course of ACD.