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

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Abstract
Fcγ receptors (FcγR) trigger inflammatory reactions in response to immunoglbulin-opsonized pathogens and antigen-antibody complexes. The coordinate expression of activating and inhibitory FcγR ensures the homeostasis of immune complex-driven inflammatory responses. In this study, we used antibodies with preferential binding for activating FcγRIIa and inhibitory FcγRIIb receptors to investigate the expression and regulation of FcγRII isoforms in human monocytes. Cross-linking of FcγRIIa triggered phagocytosis and cytokine production. Cross-linking of FcγRIIb 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 α (TNF-α), interleukin (IL)-10, and IL-13 altered the transcriptional activity of the FcγRIIB promoter in transfected cell lines and skewed the balance of activating versus inhibitory FcγR in human monocytes. TNF-α decreased the expression of inhibitory FcγRIIb. IL-10 up-regulated all classes of FcγR and induced alternative activation in monocytes, an effect that was synergistic with that of TNF-α. In contrast, IL-4 and IL-13, in combination with TNF-α, decreased the expression of activating FcγR and markedly down-regulated FcγR-mediated function. Our findings suggest that the cytokine milieu can induce changes in the relative expression of FcγR with opposing function and thus, may regulate the amplitude of FcγR-mediated uptake and inflammation.
Funding Information
  • Arthritis Foundation
  • SLE Foundation
  • National Institutes of Health (AR47106, AR49765)