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

Fc gamma receptors (Fc gamma R) trigger inflammatory reactions in response to immunoglobulin-opsonized pathogens and antigen-antibody complexes. The coordinate expression of activating and inhibitory Fc gamma R ensures the homeostasis of immune complex-driven inflammatory responses. In this study, we used antibodies with preferential binding for activating Fc gamma RIIa and inhibitory Fc gamma RIIb receptors to investigate the expression and regulation of Fc gamma RII isoforms in human monocytes. Cross-linking of Fc gamma RIIa triggered phagocytosis and cytokine production. Cross-linking of Fc gamma 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 alpha (TNF-alpha), interleakin (IL)-10, and IL-13 altered the transcriptional activity of the Fc gamma RIIB promoter in transfected cell lines and skewed the balance of activating versus inhibitory Fc gamma R in human monocytes. TNF-alpha decreased the expression of inhibitory Fc gamma RIIb. IL-10 up-regulated all classes of Fc gamma R 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 gamma R and markedly down-regulated Fc gamma R-mediated function. Our findings suggest that the cytokine milieu can induce changes in the relative expression of Fc gamma R with opposing function and thus, may regulate the amplitude of Fc gamma R-mediated uptake and inflammation.