Mononuclear phagocytes differentiate in the marrow and then pass via the blood stream to the tissues and become resident macrophages. In response to the tissue injury and inflammation, young mononuclear phagocytes pour into the affected area and in response to regulatory molecules, produced by lymphocytes or to factors derived from bacteria, undergo profound alterations in many functions. These changes in functions are vital to host defenses against tumors and microbes but can also produce massive tissue damage and destruction. A clear understanding of the physiology of macrophage development and differentiation is thus important. We plan to undertake a combined immunochemical and enzymological approach to study the significance of induction of an intracellular protein cross-linking enzyme, tissue transglutaminase in differentiation processes of the cells of monocytic lineage. The significance of tissue transglutaminase induction and its role in; a) differentiation process of monocytes and monocytic leukemia cells (THP-1) to mature macrophages, b) in acquisition of tumoricidal/microbicidal functions by monocyte and macrophages, and c) in functions such as, the ability of activated macrophages/monocytes to recognize the tumor cells and their ability to participate in antibody-dependent cell mediated cytotoxic reactions will be studied. The role of exogenous/endogenous retinoids in modulation of these functions will be studied. The role of endogenous retinoids in the differentiation process of mononuclear phagocytes will also be investigated by studying the expression of cell surface receptors for serum retinol-binding protein during different stages of development. The results obtained may be of considerable intellectual interest in terms of understanding the macrophage biology. In addition it might suggest approaches for increasing the macrophage tumoricidal and anti-infective activity in cancer and other immunocompromised patients, without an undesirable increase in macrophage/inflammatory activity or in auto-immune response.
