Fc Receptor Cross-linking Stimulates Cell Proliferation of Macrophages via the ERK Pathway*

Macrophage proliferation can be stimulated by phagocytosis and by cross-linking of Fc receptors (Fc R). In this study, we investigated the role of Fc Rand the signaling cascades that link Fc R activation to cell cycle progression. This effect was mediated by the activating Fc R, including Fc RI and III, via their Fc subunit. Further investigation revealed that the cell cycle machinery was activated by Fc R cross-linking through downstream signaling events. Specifically, we identified the extracellular signal-regulated kinase (ERK) signaling pathway as amediator of signals from Fc R activation to cyclin D1 expression, because cyclin D1 expression associated with Fc R cross-linkingwas attenuated by specific inhibitors of theERK1/2 signaling pathway, PD98059 and U0126 and the spleen tyrosine kinase (Syk) inhibitor, Piceatannol. Our findings establish a link between the ERK activation and cell cycle signaling pathways, thus providing a causal mechanism by which Fc R activation produces a mitogenic effect that stimulates macrophage proliferation. Macrophage mitosis following Fc R activation could potentially affect the outcome of macrophage interactions with intracellular pathogens. In addition, our results suggest the possibility of new treatment options for certain infectious diseases, chronic inflammatory diseases, and leukemias based on interference with Fc R-stimulated macrophage cell proliferation.