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

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 (M phi). Therefore, we applied two models of M phi differentiation, namely, culture of bone marrow cells in the presence of M-CSF and a panel of M phi cell lines ordered in a linear differentiation sequence. In both models we observed that proliferation of M phi precursors was strongly inhibited by ER-MP21. In contrast, proliferation of more mature stages of M phi differentiation was hardly affected. Remarkably, iron uptake by M phi precursor and mature M phi cell lines was inhibited by ER-MP21 to the same extent. However, mature M phi cell lines showed an iron uptake two- to threefold higher than that of M phi precursor cell lines. These observations strongly suggest that mature M phi 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 M phi is not necessarily accompanied by a higher cell surface expression of transferrin receptors, thus suggesting an increased recycling of transferrin receptors in mature M phi.