The macrophage contributes as an effector cell to both humoral and cell mediated immunity and functions in the induction of the immune response. Three major classes of phagocyte receptors have been defined on the surface of macrophages, those for antibody coated ligands, Fc receptors, for cleaved complement components, complement receptors, and a lectin-like receptor that recognizes configurations of mannose which are a ubiquitous part of the cell walls of many, pathogens, the mannose receptor (MR). The mannose receptor expression is restricted to tissue macrophages in man, rats, and mice and ligation of the receptor by pathogens occurs directly. This results in the release of biologically active molecules and the internalization of the bound particle. MR expression is a sensitive marker of the functional state of the macrophage as circulating monocytes have a high capacity to secrete reactive oxygen intermediates do not express the MR and are considered activated. Tissue macrophages have a reduced capacity to secrete reactive oxygen intermediates, express high levels of MR and are considered nonactivated. Exposure of nonactivated macrophages to macrophage activating factor(s) like interferon gamma, induces several pleiotypic changes including induction of the respiratory burst capacity and down regulation of MR expression. Our goal is understanding MR expression, which is restricted to macrophages, and uniquely reflects the functional state of the cell.
We aim a) to identify the minimal cis-acting elements of the MR gene that confer macrophage specific expression by transient and stable expression in myleomonocytic cell lines and later in transgenic mice; b) characterize and purify DNA binding proteins that constitutively regulate MR expression; c) investigate whether the interferon gamma down regulation MR activity is mediated via a specific trans-acting protein. As a first step to attaining these goals, we have fully characterized cDNAs that encode the human MR and partial clones that encode the murine analogue. In addition, we have mapped and partially characterized the 5' region of the human MR gene. We believe from a detailed study of the structure and regulation of this gene, progress in the understanding of the complex cellular systems that control macrophage function can be anticipated. This basic information may suggest novel ways in which to influence macrophage function in a) infectious disease like AIDS in which macrophage tropism appears to play a key role; b) effect macrophage mediated damage in many autoimmune and inflammatory processes.
