Uptake and intracellular handling of iron from transferrin and iron chelates by mitogen stimulated mouse lymphocytes.

The ability of lymphocytes to utilise iron from different sources has been investigated. Iron uptake from transferrin by proliferating lymphocytes gradually increased as saturation of the protein with iron was increased up to 100%, but rose sharply when addition of further iron resulted in the presence of non-transferrin bound iron. Increasing the saturation of transferrin with iron caused an increased rate of proliferation up to about 100% saturation but when the level of iron present exceeded the binding capacity of the protein, proliferation decreased and at high levels of iron it was reduced below that seen in the absence of transferrin. Comparison of the degree of iron uptake from transferrin and from iron chelators showed that the hydrophilic chelator ferric nitrilotriacetate (FeNTA) donated larger amounts of iron to cells than did transferrin or the lipophilic chelator ferric-pyridoxal isonicotinoyl hydrazone (FePIH), but did not promote proliferation, and when present in high amounts caused inhibition. In contrast, FePIH supported proliferation as efficiently as transferrin. In cells cultured with FeNTA, iron was found predominantly in an insoluble form while in the cells cultured with Fe-transferrin or FePIH the largest proportion of iron was found in the non-ferritin high molecular weight fraction, which probably represents iron in enzymes and other metabolically-important proteins. In no case did iron associated with ferritin exceed 15% of the total uptake, and the cells showed no marked increase in synthesis of ferritin in response to any of the forms of iron. These results indicate that different forms of iron are handled in different ways by lymphocytes, and that iron delivered from hydrophilic chelates may be toxic and not readily available for metabolic use. Lymphocytes appear to be poorly equipped to sequester excess iron in ferritin, and this may account for abnormalities in the immune system reported in patients with iron overload.