Cytokine-mediated regulation of activating and inhibitory Fcγ 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.

Infliximab treatment shifts the balance between stimulatory and inhibitory Fcγ receptor type II isoforms on neutrophils in patients with rheumatoid arthritis

“…Other studies have shown increased expression of activating Fc␥R on monocyte/macrophages in patients with active RA associated with enhanced monocyte effector functions in vitro (12,13), whereas increased expression of inhibitory Fc␥RIIb has been shown to prevent monocyte activation in RA (14). Studies of mouse models of RA support these findings in that strains susceptible to collagen-induced arthritis show skewed Fc␥R expression toward activating isoforms (15).…”

The Role of Activating Protein 1 in the Transcriptional Regulation of the Human FCGR2B Promoter Mediated by the -343 G → C Polymorphism Associated with Systemic Lupus Erythematosus

“…Data from our group demonstrated differential modulation of Fc␥RIIb expression in human monocytes and neutrophils by cytokines suggesting that alterations in cytokine levels common during inflammatory and autoimmune reactions could cause changes in Fc␥RIIb expression (21)(22)(23). A role for hormones in the reg- ulation of FCGR2B gene expression was revealed when dihydrotestosterone was found to inhibit Fc␥RIIb expression, suggesting a role for sex hormones in the onset and progression of autoimmune diseases (24).…”

Regulated Expression of FcγR in Human Dendritic Cells Controls Cross-Presentation of Antigen-Antibody Complexes

“…In contrast, mAb 7.3 exhibits preferential binding to Fc␥RIIb, while maintaining interaction with Fc␥RIIa (gray histograms, Fig. 1A, inset) (18). Staining with IV.3-FITC resulted in similar MFIs on iDC (51.8 Ϯ 2.9) and mDC (56.7 Ϯ 3.9) suggesting that, Fc␥RIIa expression is sustained at comparable levels at early and advanced stages of DC maturation (Fig.…”

“…Lysates obtained from Ma, iDCs, and mDCs were immunoprecipitated with pan-Fc␥RII mAb clone FLI8.26 that binds both Fc␥RIIa and Fc␥RIIb (12,19). The immunoprecipitated proteins were run on SDS-PAGE followed by immunoblotting with specific Abs raised against the intracellular domain of Fc␥RIIa (260) and Fc␥RIIb (Fc␥RIIB/IC), respectively (18). Lysates obtained from A375 melanoma cells transfected with rFc␥RIIA (IIA), Fc␥RIIB2 (IIB2), or vector only (NT) indicate the specificity of the immunoblotting Abs (Fig.…”

“…2, A, C, and D). In prior studies, we found that cross-linking of surface receptors on monocytes with 7.3 mAbs was associated with phosphorylation of the ITIM motif of Fc␥RIIb, suggesting that 7.3 mAb mediates inhibitory signaling (18). The marked decrease in phagocytosis of E-7.3 probes compared with E-IV.3 probes suggests that phagocytosis of Ab-opsonized particles can be altered by cross-linking of Fc␥RIIa and Fc␥RIIb.…”