The cytokine network and molecular events regulating the activation of macrophages, monocytes and Kupffer cells to express tumoricidal activity were investigated. We focused on the analysis of the cytokines IL 1, IFN gamma, IL 6, CSF 1, of the receptors for IL 2 and CSF 1 and of endotoxins. We demonstrated that both macrophages and monocytes express the p75 subunit of the IL 2 receptor. IL 2 could fully activate Kupffer cells and monocytes whereas IL 2 functioned only as a costimulatory agent, together with IFN gamma, in inducing cytotoxic murine macrophages. Moreover, IL 2 regulated the expression of the c-fms oncogene (the CSF I receptor) in human monocytes but not in murine macrophages. We also demonstrated that increased CSF 1 receptor expression was important for prolonged expression of tumoricidal activity by monocytes. Studies on the response of macrophages to IFN gamma, revealed that the expression of c-fos, an early activation gene, is inhibited by treatment of monocytes with IFN gamma but not with other activating agents such as IL 2 or endotoxins indicating that gene expression in response to IFN gamma may involve modulation of nuclear transactivating factors. Studies on the biochemical events associated with the response of macrophages to IFN gamma revealed a connection between tryptophan metabolism and macrophage activation. We have shown that picolinic acid, a tryptophan catabolite, which is produced by macrophages mediates some of the molecular events that follow the interaction between macrophages and IFN gamma. These findings have important clinical applications. Studies on the response of macrophages to endotoxins revealed a complex mechanism of gene expression that affects the levels of the enzyme 2'5' oligoA synthetase and of c-fms mRNA. Moreover, endotoxins elicited the expression of nuclear transactivating factors that bind the LTR of the HIV virus and are of major potential relevance for the replication of the virus in monocytes as well as for the coordinate control of gene expression during macrophage activation.
