title: Cytokine-mediated regulation of activating and inhibitory Fc gamma receptors in human monocytes.
abstract: Fc gamma receptors (Fc gammaR) trigger inflammatory reactions in response to immunoglobulin-opsonized pathogens and antigen-antibody complexes. The coordinate expression of activating and inhibitory Fc gammaR ensures the homeostasis of immune complex-driven inflammatory responses. In this study, we used antibodies with preferential binding for activating Fc gammaRIIa and inhibitory Fc gammaRIIb receptors to investigate the expression and regulation of Fc gammaRII isoforms in human monocytes. Cross-linking of Fc gammaRIIa triggered phagocytosis and cytokine production. Cross-linking of Fc gammaRIIb was associated with phosphorylation of the immunoreceptor tyrosine-based inhibitory motif and with a marked reduction in monocyte effector functions. Our study revealed that tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-10, and IL-13 altered the transcriptional activity of the Fc gammaRIIB promoter in transfected cell lines and skewed the balance of activating versus inhibitory Fc gammaR in human monocytes. TNF-alpha decreased the expression of inhibitory Fc gammaRIIb. IL-10 up-regulated all classes of Fc gammaR and induced alternative activation in monocytes, an effect that was synergistic with that of TNF-alpha. In contrast, IL-4 and IL-13, in combination with TNF-alpha, decreased the expression of activating Fc gammaR and markedly down-regulated Fc gammaR-mediated function. Our findings suggest that the cytokine milieu can induce changes in the relative expression of Fc gammaR with opposing function and thus, may regulate the amplitude of Fc gammaR-mediated uptake and inflammation.
authors.affiliation: Research Division, Hospital for Special Surgery, Department of Medicine and Graduate Program in Immunology, Weill Medical College of Cornell University, 535 East 70th Street, New York, NY 10021, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Emi
authors.initials: E
authors.lastname: Masuda
authors.forename: Marissa C
authors.initials: MC
authors.lastname: Blank
authors.forename: Kyriakos A
authors.initials: KA
authors.lastname: Kirou
authors.forename: Xiaoni
authors.initials: X
authors.lastname: Gao
authors.forename: Mee-Soon
authors.initials: MS
authors.lastname: Park
authors.forename: Luminita
authors.initials: L
authors.lastname: Pricop
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D017930:Genes, Reporter; D006801:Humans; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; C080568:Fc gamma receptor IIA; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG