The goal of these studies is to elucidate the molecular bases for the process of mononuclear phagocyte activation. Extensive work has been devoted to the analysis of the activation of human monocytes by IL 2 to a cytotoxic stage. The expression of the two subunits of the IL 2 receptor on resting and activated monocytes has been analyzed and it was found that each subunit is independently regulated by exogenous signals and utilizes different molecular mechanisms to modulate its expression. Interferon-gamma (IFNgamma) induces the IL 2Ralpha subunit by transcriptional activation of the gene, whereas IL 2 upregulates the IL 2Rbeta subunit by stabilization of the message. Subsequent studies of monocyte gene expression in response to various activators led to the formulation of a sequential activation scheme to maximize the antitumor activity of macrophages of potential relevance for clinical applications. Extension of our original observations that the activation of murine macrophages to a cytotoxic stage is related to the accumulation of ribosomal RNA precursors has led to the discovery of the potent macrophage stimulatory activity of picolinic acid. Since picolinic acid is a metabolite of tryptophan and macrophage activation is associated with tryptophan degradation, these results indicate that picolinic acid may be a physiological activator of macrophages. The analysis of gene expression in macrophages has been extended to the study of retroviral expression by studying transactivating factors modulating retroviral promotes and developing a new in vivo murine model to gain insights into the retorviral transfer from macrophages.
