Fcgamma receptor cross-linking stimulates cell proliferation of macrophages via the ERK pathway.
Macrophage proliferation can be stimulated by phagocytosis and by cross-linking of Fcgamma receptors (FcgammaR). In this study, we investigated the role of FcgammaR and the signaling cascades that link FcgammaR activation to cell cycle progression. This effect was mediated by the activating FcgammaR, including FcgammaRI and III, via their Fcgamma subunit. Further investigation revealed that the cell cycle machinery was activated by FcgammaR cross-linking through downstream signaling events. Specifically, we identified the extracellular signal-regulated kinase (ERK) signaling pathway as a mediator of signals from FcgammaR activation to cyclin D1 expression, because cyclin D1 expression associated with FcgammaR 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 FcgammaR activation produces a mitogenic effect that stimulates macrophage proliferation. Macrophage mitosis following FcgammaR 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 FcgammaR-stimulated macrophage cell proliferation.
Luo
Yong
Y
From the Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
Pollard
Jeffrey W
JW
Departments of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461; Departments of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York 10461.
Casadevall
Arturo
A
From the Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461; Departments of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461. Electronic address: arturo.casadevall@einstein.yu.edu.
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D000072377:Syk Kinase
D002070:Butadienes; D004791:Enzyme Inhibitors; C485701:Fcgr1 protein, mouse; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; D009570:Nitriles; D017452:Receptors, IgG; D013267:Stilbenes; C113580:U 0126; D019938:Cyclin D1; C041525:3,3',4,5'-tetrahydroxystilbene; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one