Differential inhibition of macrophage proliferation by anti-transferrin receptor antibody ER-MP21: correlation to macrophage differentiation stage

textabstractAbstract Monoclonal antibodies (mAbs) directed against the transferrin receptor are known to inhibit proliferation of cells due to iron deprivation. Some cell types, however, escape from growth inhibition by a mechanism which is unclear at present. This mechanism is the subject of the present study. We investigated the differential growth inhibition caused by anti-transferrin receptor mAb ER-MP21 in connection with the differentiation of murine macrophages (Mφ). Therefore, we applied two models of Mφ differentiation, namely, culture of bone marrow cells in the presence of M-CSF and a panel of Mφ cell lines ordered in a linear differentiation sequence. In both models we observed that proliferation of Mφ precursors was strongly inhibited by ER-MP21. In contrast, proliferation of more mature stages of Mφ differentiation was hardly affected. Remarkably, iron uptake by Mφ precursor and mature Mφ cell lines was inhibited by ER-MP21 to the same extent. However, mature Mφ cell lines showed an iron uptake two-to threefold higher than that of Mφ precursor cell lines. These observations strongly suggest that mature Mφ escape from ER-MP21-mediated growth inhibition, because these cells take up more iron than is actually needed for proliferation. Furthermore, we found that enhanced iron uptake by mature Mφ is not necessarily accompanied by a higher cell surface expression of transferrin receptors, thus suggesting an increased recycling of transferrin receptors in mature Mφ