TY - JOUR
T1 - Fcγ receptor cross-linking stimulates cell proliferation of macrophages via the ERK pathway
AU - Luo, Yong
AU - Pollard, Jeffrey W.
AU - Casadevall, Arturo
PY - 2010/2/5
Y1 - 2010/2/5
N2 - Macrophage proliferation can be stimulated by phagocytosis and by cross-linking of Fcγ receptors (FcγR). In this study, we investigated the role of FcγR and the signaling cascades that link FcγR activation to cell cycle progression. This effect was mediated by the activating FcγR, including FcγRI and III, via their Fcγ subunit. Further investigation revealed that the cell cycle machinery was activated by FcγR cross-linking through downstream signaling events. Specifically, we identified the extracellular signal-regulated kinase (ERK) signaling pathway as a mediator of signals from FcγR activation to cyclin D1 expression, because cyclin D1 expression associated with FcγR cross-linking was attenuated by specific inhibitors of the ERK1/2 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 FcγR activation produces a mitogenic effect that stimulates macrophage proliferation. Macrophage mitosis following FcγR 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 FcγR-stimulated macrophage cell proliferation.
AB - Macrophage proliferation can be stimulated by phagocytosis and by cross-linking of Fcγ receptors (FcγR). In this study, we investigated the role of FcγR and the signaling cascades that link FcγR activation to cell cycle progression. This effect was mediated by the activating FcγR, including FcγRI and III, via their Fcγ subunit. Further investigation revealed that the cell cycle machinery was activated by FcγR cross-linking through downstream signaling events. Specifically, we identified the extracellular signal-regulated kinase (ERK) signaling pathway as a mediator of signals from FcγR activation to cyclin D1 expression, because cyclin D1 expression associated with FcγR cross-linking was attenuated by specific inhibitors of the ERK1/2 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 FcγR activation produces a mitogenic effect that stimulates macrophage proliferation. Macrophage mitosis following FcγR 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 FcγR-stimulated macrophage cell proliferation.
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U2 - 10.1074/jbc.M109.037168
DO - 10.1074/jbc.M109.037168
M3 - Article
C2 - 19996316
AN - SCOPUS:77950496491
SN - 0021-9258
VL - 285
SP - 4232
EP - 4242
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
ER -