Migration inhibitory factors and macrophage differentiation.

It has been described before that only certain types of macrophages are capable to respond to lymphokines and that only certain macrophage phenotypes were able to migrate and to respond to migration inhibitory factors (MIF). With respect to the dissociation of MIF activities from a series of other biological activities, and with regard to the phenotype-associated response of macrophages to MIF it was asked: What are the characteristics of the MIF-responsive macrophage phenotype and what are the functional changes induced by MIF on macrophages in addition to inhibition of random migration? Bone marrow-derived macrophages on day 6 of culture were separated by hypotonic Percoll density gradient centrifugation into three distinct bands and analyzed for a variety of functions. It was found that migrating and MIF-responsive macrophages accumulate at a certain density. These macrophages were further characterized by monoclonal antibodies generated against murine macrophage phenotypes. One marker was found to be preferentially expressed by MIF-responsive macrophages. In order to study the inducibility of MIF responsiveness, bone marrow-derived macrophages on day 16 of culture which were poorly migrating and did not respond to MIF were induced to proliferate by the addition of L cell-conditioned medium. After proliferation had subsided, MIF sensitivity was restored. The effects of MIFs other than migration inhibition, on a number of functions which had been mapped within the cell cycle, were investigated. It was found that MIF acts anti-proliferative on "young", cycling macrophages. Non-cycling, mature macrophages were shifted to a state characterized by a decreased expression of transglutaminase and plasminogen activator and an increase of certain phenotypic surface markers. It is concluded that MIFs are differentiation-inducing signals, acting on the generation of macrophages from precursors but also in the recruitment of terminally differentiated macrophages to "inflammatory" type of macrophages which are functional in the induction of immune responses.