Blockage of the Early Events of Mitogenic Signaling by Interferon-γ in Macrophages in Response to Colony-Stimulating Factor-1

Inhibition of cell proliferation is an important biologic funcphorbol ester, as measured by early gene expression, DNA tion of interferons (IFNs), which has been exploited in therasynthesis and cell proliferation. Although activation, phospeutic treatment of certain hematologic malignancies. Howphorylation, and turnover of the CSF-1 receptor and CSF-1-ever, the molecular mechanism was not clear. We have induced increase in diacylglycerol production remained norrecently shown that IFNs (alpha /beta and gamma ) inhibit protein kinase mal, IFN-gamma blocked CSF-1-stimulated activation of mitogen-C (PKC)-dependent (such as PDGF and phorbol ester) but activated protein kinases, Raf-1 kinase, increase in GTP-not PKC-independent (such as epidermal growth factor) actibound Ras and tyrosine phosphorylation, and activation of vation of Raf-1 and mitogen-activated protein kinases protein kinase C delta (PKC-delta ). PKC-delta was required for CSF-1-(MAPK/ERKs) in fibroblasts (Xu et al, Mol Cell Biol 14:8018, induced mitogenic signaling and a primary target for IFN-gamma - 1994), suggesting a novel mechanism by which IFNs execute induced inhibition. Interestingly, although phorbol myristate their antiproliferative function. Monocytes/macrophages acetate stimulated Ras activation, PKC-delta did not appear to are primary targets in vivo for IFN-gamma , the major activity of be an upstream activator of Ras. These studies clearly indimacrophage-activating factor. In the present study, mechacated that IFN-gamma specifically inhibits PKC-delta activation, renism of IFN-gamma-induced antiproliferative action in macrosulting in blockage of the early events of mitogenesis in phages in response to colony-stimulating factor-1 (CSF-1) macrophages in response to CSF-1