This laboratory has been focusing its efforts on the biochemical and molecular events which occur upon macrophage activation. Studies were performed on macrophage cell lines immortalized by recombinant retroviruses expressing the oncogenes v-myc and v- raf. It has been demonstrated that macrophage lines retain the ability to express, constitutively or upon stimulation, the immunoregulatory and effector functions of normal peritoneal macrophages. The expression of the proto-oncogene c-fos, was also induced by activators of protein kinase C (PK-C) with modalities similar to normal macrophages. These results indicated that expression of viral oncogenes does not affect macrophage function and thus establishes these cell lines as suitable for investigation of the molecular basis of macrophage function. We have previously demonstrated a clear association between accumulation of ribosomal RNA precursors and expression of cytotoxic activity by macrophages. We have now found that this molecular event is a common endpoint to the pathways of macrophage activation induced by interferon alpha, beta, or gamma. Additional experiments have revealed, however, that IFN beta and gamma differ in their effects upon c-fos activation indicating that the initial steps involved in macrophage activation by these agents may differ. Based on our studies on the expression of the c-fos proto- oncogenes in macrophages, we have designed experiments aimed at the understanding the relationship between transforming oncogenes and the c-fos proto-oncogene. These studies have revealed that cells transformed by Ha-ras, but not Ki or N-ras, lose the ability to express c-fos in response to PKC activators. These data indicated that the mechanism of cellular transformation by H-ras may involve deregulation of c-fos functions as a consequence of altered cellular responses to external stimuli.
