Cytokine-mediated regulation of activating and inhibitory Fc receptors in human monocytes

Fc receptors (Fc R) trigger inflammatory reactions in response to immunoglobulinopsonized pathogens and antigen-antibody complexes. The coordinate expression of activating and inhibitory Fc R ensures the homeostasis of immune complex-driven inflammatory responses. In this study, we used antibodies with preferential binding for activating Fc RIIa and inhibitory Fc RIIb receptors to investigate the expression and regulation of Fc RII isoforms in human monocytes. Cross-linking of Fc RIIa triggered phagocytosis and cytokine production. Cross-linking of Fc RIIb 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 (TNF), interleukin (IL)-10, and IL-13 altered the transcriptional activity of the Fc RIIB promoter in transfected cell lines and skewed the balance of activating versus inhibitory Fc R in human monocytes. TNFdecreased the expression of inhibitory Fc RIIb. IL-10 up-regulated all classes of Fc R and induced alternative activation in monocytes, an effect that was synergistic with that of TNF. In contrast, IL-4 and IL-13, in combination with TNF, decreased the expression of activating Fc R and markedly downregulated Fc R-mediated function. Our findings suggest that the cytokine milieu can induce changes in the relative expression of Fc R with opposing function and thus, may regulate the amplitude of Fc R-mediated uptake and inflammation. J. Leukoc. Biol. 77: 767–776; 2005.