S D Somers

Biochemical models of interferon-γ-mediated macrophage activation: Independent regulation of lymphocyte function associated antigen (LFA)-1 and I-A antigen on murine peritoneal macrophages

IFN-gamma can induce the expression of both class II histocompatibility antigens (Ia) and the lymphocyte function associated (LFA)-1 antigen on murine peritoneal macrophages. We have examined the molecular changes which lead to altered expression of these two cell surface proteins to determine whether they are regulated by similar or independent mechanisms. While I-A antigen expression can be induced or enhanced by treatment of macrophages with either phorbol diesters and/or the Ca2+ ionophore A23187, these agents had no effect upon expression of LFA-1 under similar conditions. Macrophages from the A/J strain mouse exhibit a deficiency in their sensitivity to IFN-gamma which is seen in our studies as an inability of IFN-gamma to elevate I-A antigen expression. However, expression of I-A could be modulated in these cells by treatment with either phorbol diesters or A23187. In contrast, IFN-gamma could induce LFA-1 antigen on A/J derived macrophages and this was not affected by either phorbol or A23187. Thus these two antigens, despite coordinate expression in response to IFN-gamma in normal mouse strains, are clearly regulated independently. These results suggest that IFN-gamma generates at least two independent molecular events in macrophages which ultimately modulate the expression of cell surface proteins important to the performance of activated functions.

Expression and Development of Macrophage Activation for Tumor Cytotoxicity

Mononuclear phagocytes of the tissues, when exposed to the numerous humoral mediators found at sites of inflammation, and particularly when exposed to lymphokines, undergo profound alterations in their cellular physiology (for review, see Adams and Marino, 1984). These intricate, tightly coordinated changes in metabolism and structure, broadly termed activation even though they are often defined in more restrictive ways, are essential to the contributions made by mononuclear phagocytes in maintenance of homeostasis, in metabolism of endogenous and exogenous toxins, in regulation of inflammation, and in the immune response and defense against tumors and microbes. Since the metabolic consequences of inductive signals leading to activation are extremely complex, examination of macrophage activation for a single function can provide a useful model for studying the cell biology of activation (Adams and Marino, 1984).

AUGMENTED BINDING OF TUMOR CELLS BY ACTIVATED MURINE MACROPHAGES AND ITS RELEVANCE TO TUMOR CYTOTOXICITY

Publisher Summary This chapter examines the augmented binding of tumor cells by activated murine macrophages and its relevance to tumor cytotoxicity. Macrophages activated by a variety of infectious agents are able to destroy tumor cells efficiently in vitro. Macrophage-mediated cytotoxicity is target selective, as neoplastically transformed cells are lysed in preference to their nontransformed counterparts. Both microscopic and cine-microscopic observations of activated MΦ-tumor cell cultures have further revealed clustering of activated MΦ about tumor cells that are lysed. Macrophages activated in a variety of ways in vivo and in vitro selectively bind neoplastic targets to an augmented degree. The augmented binding, which is inhibited by plasma membranes of tumor cells, is saturable, competitively inhibitable, and dependent upon trypsinsensitive surface components and has two functional consequences, which include cytolysis of the bound targets and secretion of a lytic proteinase. The augmented binding, thus, has many characteristics of the specific interaction between ligand and receptor. The low-level binding seen between numerous cell pairs in culture has many characteristics of nonspecific binding. The capacity for augmented binding is mediated by receptors on the macrophages for structures contained within the plasma membranes of neoplastic cells.