FcgammaRI Expression Research Articles

Effect of recombinant IFN-gamma (rIFN-gamma) on the mechanism of human macrophage IgG FcRI-mediated cytotoxicity. rIFN-gamma decreases inhibition by cytophilic human IgG and changes the cytolytic mechanism.

Different classes of receptors for the Fc moiety of IgG (Fc gamma R) have been defined on human monocytes and macrophages: Fc gamma RI, Fc gamma RII, and Fc gamma RIII. All three classes are capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). Fc gamma RI, which binds monomeric human IgG (hIgG) with high affinity, was shown an effective cytotoxic trigger molecule on different types of cells. In vitro, the inhibition of Fc gamma RI-mediated ADCC by hIgG is well documented. The low affinity receptor classes, Fc gamma RII and Fc gamma RIII, are not blocked by monomeric hIgG. Because monomeric hIgG is present at high concentrations in plasma and interstitial fluids it has been postulated inhibitory in vivo. We investigated the effect of rIFN-gamma on macrophage Fc gamma RI-mediated ADCC in the presence of low doses hIgG. With human E sensitized with hIgG as target cells, Fc gamma RI was studied selectively. We found that rIFN-gamma enhances both expression and cell surface density of Fc gamma RI on cultured peripheral blood monocytes. Furthermore, this cytokine partially reversed the inhibitory effect of monomeric hIgG on ADCC. More interestingly, we found that the cytolytic mechanism of monocyte-derived macrophages changed completely after prolonged culture with rIFN-gamma. Monocytes cultured for 9 days in control medium mediate predominantly phagocytosis. After long term rIFN-gamma stimulation (9 days), monocyte-derived macrophages almost completely lost the capacity to perform phagocytosis. Interestingly, they became highly efficient in mediating extracellular lysis of human E sensitized with hIgG. Short term rIFN-gamma stimulated monocyte-derived macrophages (for the last 40 h of culture) were found to mediate both phagocytosis and extracellular lysis. Our findings suggest that in vivo rIFN-gamma-stimulated macrophages may be most efficient in Fc gamma RI-mediated cytolysis as a consequence of a changed cytolytic mechanism in combination with enhanced Fc gamma RI density.

Altered function and surface marker expression of neutrophils induced by rhG-CSF treatment in severe congenital neutropenia.

Neutrophils from patients suffering from severe congenital neutropenia (SCN), who were receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF), were investigated in order to analyze the previously described decrease in chemotaxis. This study demonstrated the decreased chemotaxis to five well-known chemoattractants, FMLP, C5a, IL-8, LTB4 and PAF. To further investigate this impairment of patients' neutrophils, receptors and receptor turnover for chemoattractants were examined using flow cytometry. We found 1) increased FMLP receptor and decreased C5a receptor expression, 2) a normal expression of intracellular FMLP receptors after incubation with PMA, 3) increased loss and decreased re-expression of FMLP receptors after incubation with this peptide, 4) normal expression of adhesion glycoproteins CR3 (CD11b/CD18) and LFA1 (CD11a/CD18), 5) further signs of in vivo preactivation: high expression of Fc gamma-RI (CD64) and Fc gamma-RII (CD32), decreased expression of Fc gamma-RIII (CD16), increased expression of CD14, and low expression of HLA-DR. These data demonstrate that the decrease of chemotaxis of neutrophils from SCN patients is not due: a) to a decrease in the number of intra- or extracellular FMLP receptors; b) to a decrease of adhesion molecules. However, the decreased chemotaxis could result from an altered FMLP receptor turnover. The relevance of the altered Fc gamma-receptor pattern for the in vivo occurrence of side-effects, e.g. the necrotic vasculitis, of G-CSF treatment is discussed.

Ligand-sensitive binding of actin-binding protein to immunoglobulin G Fc Receptor I (FcγRI)

The high affinity receptor that binds the Fc domain of immunoglobulin G (IgG) subclasses 1 and 3 (Fc gamma RI) mediates important immune defense functions by inducing cell surface changes on human leukocytes. In this article, we document direct high affinity binding of Fc gamma RI to the actin filament cross-linking protein, actin-binding protein (ABP). In the absence of IgG, all Fc gamma RI molecules in undifferentiated cells of myeloid line U937 bound to ABP over a 9-fold range of Fc gamma RI expression induced by human IFN-gamma. Binding of IgG to U937 cells constitutively expressing Fc gamma RI or to COS cells genetically transfected to express Fc gamma RI rapidly decreased the avidity of Fc gamma RI for ABP. This finding suggests the existence of a pathway communicating a signal between a functional IgG receptor and intracellular components involved in the effector responses to Fc gamma RI-ligand interaction.

Neutrophils Express the High Affinity Receptor for IgG (FcγRI, CD64) After In Vivo Application of Recombinant Human Granulocyte Colony-Stimulating Factor

Fc receptors are important effector molecules of neutrophilic granulocytes (polymorphonuclear neutrophils [PMN]), connecting phagocytic cells and the specific immune response. Neutrophils from healthy donors express the low-affinity receptors for IgG Fc gamma RII (CD32) and Fc gamma RIII (CD16), but not the high-affinity receptor Fc gamma RI (CD64). The latter has been found on neutrophils from patients with certain bacterial infections and can be induced in vitro after incubation with interferon-gamma. We show here that neutrophils strongly express Fc gamma RI after in vivo application of recombinant human granulocyte colony-stimulating factor (rhG-CSF). PMN from patients receiving rhG-CSF displayed higher cytotoxicity against Daudi lymphoma cells in vitro compared with control patients and with healthy donors. Fab fragments against Fc gamma RII (monoclonal antibody [MoAb] IV.3) inhibited neutrophil-mediated cytotoxicity of healthy donors but not of patients during rhG-CSF therapy. Therefore, expression of Fc receptors by PMN was investigated by flow cytometry and the mean fluorescence intensity (MFI) was compared. After staining with MoAb 32.2 against Fc gamma RL, the median MFI of neutrophils from G-CSF patients (median, 4.78; range, 2.40 to 8.50; n = 5) was significantly higher (P = .002 and P = .001, respectively) than the median MFI of patients not receiving G-CSF (median, 1.23; range, 1.01 to 1.58; n = 6) and the median MFI of healthy donors (median, 1.04; range, 0.67 to 1.12; n = 6). Fc gamma RI disappeared after the discontinuing of the G-CSF injections, but was reinduced during the next treatment cycle with rhG-CSF. The high expression of Fc gamma RI during rhG-CSF therapy correlated with enhanced cytotoxicity. In vitro incubation with rhG-CSF also enhances cytotoxicity, but only minor increments in Fc gamma RI expression were observed. Thus, during in vivo application of rhG-CSF neutrophils acquire an additional potent receptor for mediating tumor cell killing in vitro by induction of the high-affinity receptor for IgG (Fc gamma RI, CD64).

Neutrophils express the high affinity receptor for IgG (Fc gamma RI, CD64) after in vivo application of recombinant human granulocyte colony- stimulating factor

Fc receptors are important effector molecules of neutrophilic granulocytes (polymorphonuclear neutrophils [PMN]), connecting phagocytic cells and the specific immune response. Neutrophils from healthy donors express the low-affinity receptors for IgG Fc gamma RII (CD32) and Fc gamma RIII (CD16), but not the high-affinity receptor Fc gamma RI (CD64). The latter has been found on neutrophils from patients with certain bacterial infections and can be induced in vitro after incubation with interferon-gamma. We show here that neutrophils strongly express Fc gamma RI after in vivo application of recombinant human granulocyte colony-stimulating factor (rhG-CSF). PMN from patients receiving rhG-CSF displayed higher cytotoxicity against Daudi lymphoma cells in vitro compared with control patients and with healthy donors. Fab fragments against Fc gamma RII (monoclonal antibody [MoAb] IV.3) inhibited neutrophil-mediated cytotoxicity of healthy donors but not of patients during rhG-CSF therapy. Therefore, expression of Fc receptors by PMN was investigated by flow cytometry and the mean fluorescence intensity (MFI) was compared. After staining with MoAb 32.2 against Fc gamma RL, the median MFI of neutrophils from G-CSF patients (median, 4.78; range, 2.40 to 8.50; n = 5) was significantly higher (P = .002 and P = .001, respectively) than the median MFI of patients not receiving G-CSF (median, 1.23; range, 1.01 to 1.58; n = 6) and the median MFI of healthy donors (median, 1.04; range, 0.67 to 1.12; n = 6). Fc gamma RI disappeared after the discontinuing of the G- CSF injections, but was reinduced during the next treatment cycle with rhG-CSF. The high expression of Fc gamma RI during rhG-CSF therapy correlated with enhanced cytotoxicity. In vitro incubation with rhG-CSF also enhances cytotoxicity, but only minor increments in Fc gamma RI expression were observed. Thus, during in vivo application of rhG-CSF neutrophils acquire an additional potent receptor for mediating tumor cell killing in vitro by induction of the high-affinity receptor for IgG (Fc gamma RI, CD64).

Monokines released during short-term Fc gamma receptor phagocytosis up-regulate polymorphonuclear leukocytes and monocyte-phagocytic function.

Freshly explanted monocytes phagocytosing IgG antibody-coated erythrocyte targets (EIgG) release a factor(s) that stimulates phagocytosis by neighboring monocytes and polymorphonuclear leukocytes (PMN). Culture supernatants obtained after 30-min incubation of adherent monocytes with EIgG, but not unopsonized sheep erythrocytes, markedly up-regulated the extent of PMN phagocytosis and enhanced the rate at which monocytes ingested EIgG. The presence of this factor(s) was first evident in phagocytic studies in which monocytes were prepared by a colloidal silica-based continuous gradient technique (Sepracell-Mn). After introduction of erythrocyte targets, there was a 20- to 30-min delay before initiation of phagocytosis that was not observed with monocytes prepared by the standard Percoll-gradient technique. Experiments suggest that, when compared with monocytes prepared by the Percoll-gradient method, Sepracell-Mn monocytes are closer to a base line state of activation with regard to the expression of Fc gamma RI and the ability to ingest EIgG. The mechanism of PMN upregulation by the monocyte factor(s) was explored. Monocyte supernatants did not induce an increase in the surface expression of PMN Fc gamma RI, II, or III. Neither anti-TNF, anti-IL-2, nor anti-GM-CSF had any significant effect on monocyte supernatant activity. Neutrophil activating protein-1 was not detected by ELISA. In contrast, anti-IL-1 completely blocked the effect of the supernatant on subsequent monocyte phagocytosis, and partially inhibited its effect on PMN phagocytosis. Furthermore, it was shown that RIL-1 as well as TNF markedly enhanced monocyte and PMN ingestion of EIgG. These results suggest that monocytes, after Fc gamma R-mediated phagocytosis, release monokines, including at least IL-1, which enhance the phagocytic function of neighboring PMN and monocytes to augment the host defense process.

Localization of three subtypes of Fcγ receptors in human placenta by immunohistochemical analysis

We investigated the localization of the three subtypes of (Fc gamma R) in the normal human placenta using immunohistochemical and immunocytochemical techniques with specific monoclonal antibodies. The analysis revealed that Fc gamma RI was expressed on Hofbauer cells, that Fc gamma RII was expressed on Hofbauer cells and endothelial cells of fetal vessels, while Fc gamma RIII was expressed on trophoblasts, especially syncytiotrophoblasts. Moreover, we demonstrated that the expression of Fc gamma RI and Fc gamma RII on Hofbauer cells and endothelial cells of the fetal vessels in the 1st trimester placenta was different from that in the 3rd trimester placenta. These results, therefore, indicate that the three subtypes of Fc gamma R in the human placenta may contribute to maintenance of placental functions, because each Fc gamma R molecule displays unique biological functions similar to those on leukocytes.

Monocytes and polymorphonuclear neutrophils of patients with streptococcal pharyngitis express increased numbers of type I IgG Fc receptors.

Studies using cultured cells have shown that gamma interferon (IFN-gamma) induces the expression of Fc gamma RI (the type I Fc receptor for IgG) on human polymorphonuclear neutrophils (PMN) and greatly increases the number of these receptors on human monocytes. Administration of rIFN-gamma in vivo also causes enhanced Fc gamma RI expression on these cell populations. Because streptococcal antigens are potent inducers of IFN-gamma in vitro, we postulated that IFN-gamma would be produced endogenously in vivo in patients with streptococcal infections. Such production of IFN-gamma in vivo, even at low levels, might be expected to induce the expression of Fc gamma RI on monocytes and neutrophils. To evaluate this possibility, we used monoclonal antibody 32 (mAb 32), which is specific for Fc gamma RI, to quantitate the expression of this receptor on human peripheral blood cells. We measured the binding of mAb 32 to monocytes and PMNs isolated from healthy donors and from patients with group A beta-hemolytic streptococcal (GABHS) pharyngitis. PMNs from healthy donors (n = 12) had 700 +/- 600 (mean +/- SD) mAb 32 binding sites. Patients with pharyngitis and negative throat culture for GABHS (n = 11) had 2,100 +/- 1,600 sites on their PMNs. In contrast, the PMNs from patients with documented GABHS pharyngitis (n = 12) had 11,600 +/- 7,500 mAb 32 binding sites on their surface. There was a similar change in the expression of Fc gamma RI on monocytes, with control monocytes having a mean of 19,900 +/- 3,200 mAb 32 binding sites per cell and the GABHS-positive monocytes having 47,500 +/- 21,400 sites. The GABHS-negative throat culture group had a slightly elevated number of Fc gamma RI with a mean of 28,200 +/- 8,400 sites. 10 patients with documented urinary tract infections and three patients with uncomplicated pyelonephritis had no elevation in Fc gamma RI expression. These studies demonstrate that a localized group A streptococcal infection can cause systemic activation of the entire circulating pool of phagocytes, and suggest that a similar level of activation is uncommon in localized gram-negative infections of the urinary tract.

Regulation of the steady state level of Fc gamma RI mRNA by IFN-gamma and dexamethasone in human monocytes, neutrophils, and U-937 cells.

The high affinity IgG FcR Fc gamma RI, CD64, plays important roles in the immune response. Fc gamma RI is predominantly expressed on monocytes and macrophages, and barely detectable on neutrophils. rIFN-gamma markedly increases the expression of Fc gamma RI on neutrophils, monocytes, macrophages and myeloid cell lines such as U-937, HL-60, and THP-1. Glucocorticoids inhibit the augmentation of Fc gamma RI expression by rIFN-gamma on neutrophils and myeloid cell lines, but enhance the augmentation of Fc gamma RI expression by rIFN-gamma on monocytes. In this study, we examined the effect of rIFN-gamma and dexamethasone (Dex) on the steady state level of Fc gamma RI mRNA in U-937 cells, neutrophils, and monocytes by hybridizing total RNA with the Fc gamma RI cDNA probe, p135. We found that the amount of Fc gamma RI mRNA increased within 1 h of treatment with rIFN-gamma in all three cell types. This initial induction of Fc gamma RI mRNA by rIFN-gamma was completely blocked by an inhibitor of RNA synthesis, actinomycin D, suggesting that the rIFN-gamma-mediated induction of Fc gamma RI mRNA is dependent on gene transcription. Dex, used in combination with rIFN-gamma, partially blocked the induction of Fc gamma RI mRNA by rIFN-gamma in U-937 cells and neutrophils, but caused a synergistic increase in Fc gamma RI mRNA levels in monocytes. The inhibitory effect of Dex on the steady state level of Fc gamma RI mRNA in U-937 cells was blocked by an inhibitor of protein synthesis, cycloheximide, suggesting that Dex-induced proteins were involved in the regulation of Fc gamma RI expression. This study indicates that the regulation of Fc gamma RI expression on U-937 cells, neutrophils, and monocytes by rIFN-gamma and Dex occurs, at least in part, at the mRNA level. rIFN-gamma increases the steady state level of Fc gamma RI mRNA through a common pathway among U-937 cells, neutrophils, and monocytes, whereas the effect of Dex on rIFN-gamma-induced Fc gamma RI mRNA is cell-type specific.

IL-4 decreases Fc gamma R membrane expression and Fc gamma R-mediated cytotoxic activity of human monocytes.

Monocytes can express three classes of FcR for IgG: Fc gamma RI, Fc gamma RII, and Fc gamma RIII (CD64, CD32, and CD16, respectively) of which the Fc gamma RIII is expressed after prolonged culture. Fc gamma R expression is regulated by IFN-gamma. Because IFN-gamma and IL-4 have antagonistic effects on the expression of the FcR for IgE on human monocytes, we studied the effect of IL-4 on Fc gamma R expression and function. We show that IL-4 down-regulates Fc gamma RI, Fc gamma RII, and Fc gamma RIII expression of cultured monocytes and inhibits IFN-gamma enhanced Fc gamma RI expression. Exposure of monocytes to IL-4 for 40 h resulted in a dose-dependent decrease of the expression of all three Fc gamma R that persisted throughout the whole culture period (7 days). Anti-IL-4 antibodies completely reversed the IL-4 effect. In addition the impaired Fc gamma R expression correlated directly with reduced Fc gamma R-mediated function because monocytes cultured in the presence of IL-4 have a reduced capacity to lyse human E opsonized with human IgG anti-D or mouse antiglycophorin A antibodies. These observations, together with the previous finding that IL-4 induces Fc epsilon RIIb expression on monocytes, indicate that IL-4 and IFN-gamma may control the Fc gamma R-mediated immune response by differentially regulating Fc gamma R expression.

Cross-linking of both Fc gamma RI and Fc gamma RII induces secretion of tumor necrosis factor by human monocytes, requiring high affinity Fc-Fc gamma R interactions. Functional activation of Fc gamma RII by treatment with proteases or neuraminidase.

Cross-linking of Fc gamma R on human monocytes with human IgG has been shown to induce secretion of the inflammatory and immunoregulatory cytokine TNF. In the present study we examined the role of both constitutively expressed monocyte Fc gamma R, the 72-kDa high affinity Fc gamma R (Fc gamma RI), and the 40-kDa low affinity receptor (Fc gamma RII), in the induction of TNF secretion. On the basis of preferential binding of the Fc moiety of murine mAb of different isotype, Fc gamma RI and Fc gamma RII were selectively cross-linked by using either solid-phase murine (m)IgG2a, or solid-phase mIgG1, respectively. On freshly isolated, untreated monocytes only cross-linking of Fc gamma RI with solid-phase mIgG2a induced TNF secretion. The interaction between Fc gamma RII and mIgG1 could be enhanced by treatment of monocytes with proteases or with the desialylating enzyme neuraminidase. After treatment of monocytes with these enzymes, TNF secretion was effectively induced by solid-phase mIgG1, apparently through cross-linking of Fc gamma RII. However, mIgG1-induced TNF secretion differed between protease-treated monocytes from high responder individuals and monocytes from low responder individuals, TNF secretion being considerably less in the latter population. Protease-treated monocytes and mononuclear cells from individuals with an inherited defect in cell membrane expression of Fc gamma RI were induced to secrete TNF by solid-phase human IgG, confirming the capacity of Fc gamma RII to induce TNF secretion. It was not possible to induce TNF secretion by cross-linking Fc gamma RI or Fc gamma RII with anti-Fc gamma R mAb and soluble or solid-phase anti-mIgG, indicating that high affinity Fc-Fc gamma R interactions are necessary to induce release of this cytokine.

Regulation of Fc gamma receptor expression and phagocytosis of a human monoblast cell line U937. Participation of cAMP and protein kinase C in the effects of IFN-gamma and phorbol ester.

We investigated the positive and negative effects of IFN-gamma, PMA, dibutyryl cAMP (Bt2cAMP), dexamethasone and transforming growth factor-beta (TGF-beta) on Fc gamma R subtype expression and phagocytosis of a human monoblast cell line, U937. IFN-gamma increased and Bt2cAMP decreased Fc gamma RI expression determined by a mAb 32.2, whereas PMA and Bt2cAMP increased Fc gamma RII expression determined by a mAb IV-3. Phagocytosis was measured microscopically by counting ingested aggregated human IgG- or BSA-treated ox E (Eo'-IgG or Eo'-BSA). IFN-gamma increased the phagocytosis of Eo'-IgG but not that of Eo'-BSA, and PMA increased the phagocytosis of both Eo'-IgG and Eo'-BSA. Bt2cAMP decreased both basal and IFN-gamma- and PMA-augmented phagocytosis of U937 cells. Dexamethasone also inhibited both basal and IFN-gamma-augmented Fc gamma RI expression and PMA-augmented Fc gamma RII expression and phagocytosis, but did not affect IFN-gamma-augmented phagocytosis of Eo'-IgG. The augmentation of phagocytosis of Eo'-IgG by IFN-gamma thus seems to be due mainly to the increased internalizing process rather than to increased Fc gamma RI expression. TGF-beta slightly decreased Fc gamma R expression. In a study of the participation of protein kinase C (PK-C), it was found that H-7, a PK-C inhibitor, did not inhibit either IFN-gamma- or PMA-enhanced Fc gamma RI and Fc gamma RII expression, respectively, and 1-oleoyl-2-acetylglycerol and N-(6-phenylhexyl)-5-chloro-1-naphthalenesulfonamide, both PK-C activators, did not show any apparent increase in Fc gamma R expression and phagocytosis. These results show that Fc gamma RI and Fc gamma RII expression on U937 cells is regulated by different mechanisms and that IFN-gamma and PMA play their roles in Fc gamma R expression and phagocytosis by different pathways. It is possible that cAMP but not PK-C plays an important role in the regulation of Fc gamma R expression and phagocytosis.

Fc gamma R-mediated killing by eosinophils.

In this report we present data on the ability of the different Fc gamma R present on eosinophils to mediate killing of erythroid and tumor targets, and on a comparison of eosinophil and neutrophil Fc gamma R-mediated killing. Erythroid target killing was assessed using chicken erythrocytes (CE) and heteroantibodies composed of Fab fragments of anti-CE antibodies covalently coupled to Fab fragments of anti-Fc gamma R antibodies. Such anti-CE x anti-Fc gamma R reagents permit linkage of CE target cells with the FcR molecules on the eosinophil or neutrophil effector cells. Tumor target killing was assessed using hybridoma cell lines (HC) bearing anti-Fc gamma R antibodies on their cell surface. Freshly isolated eosinophils and neutrophils constitutively express similar amounts of the low affinity Fc gamma R, Fc gamma RII on their cell surface, but neither cell type expresses the high affinity Fc gamma R, Fc gamma RI. In contrast, eosinophils have only about 5% as much of the low affinity Fc gamma R found on human granulocytes and large granular lymphocytes (Fc gamma RIII) as neutrophils. Untreated, freshly prepared eosinophils or neutrophils did not lyse any of the anti-Fc gamma R bearing HC nor did they lyse CE in the presence of anti-Fc gamma R containing heteroantibodies. Upon treatment with granulocyte monocyte-CSF (GM-CSF), both cell types lysed HC-bearing antibody to Fc gamma RII (HC IV.3A) and CE in the presence of anti-CE x anti-Fc gamma RII heteroantibodies. However, neither cell type lysed HC-bearing antibody to Fc gamma RI or Fc gamma RIII, or CE in the presence of anti-CE x anti-Fc gamma RI HA. Treatment with GM-CSF did not significantly alter the number of Fc gamma R on either cell type. Treatment of neutrophils with IFN-gamma for 18 h induced the expression of Fc gamma RI on these cells and their ability to lyse anti-Fc gamma RI- or Fc gamma RII-bearing HC and CE through Fc gamma RI, Fc gamma RII, and Fc gamma RIII. In contrast, 6-h treatment of eosinophils or neutrophils with IFN-gamma induced neither Fc gamma RI expression on either cell type nor killing of HC or CE through Fc gamma R. In summary, incubation with GM-CSF, induced eosinophils and neutrophils to kill anti-Fc gamma RII-bearing HC and to lyse CE through Fc gamma RII. This augmented killing was not associated with enhanced expression of Fc gamma RII.(ABSTRACT TRUNCATED AT 400 WORDS)

Modulation of the human monocyte binding site for monomeric immunoglobulin G by activated Hageman factor.

Macrophage Fc gamma receptors play a significant role in inflammation and host defense. One monocyte/macrophage Fc gamma receptor, Fc gamma RI, the binding site for monomeric IgG, appears to be especially responsive to modulatory signals by hormones and mediators. Since Factor XIIa is generated during inflammation, we studied the effect of XIIa on Fc gamma RI. Factor XIIa, in a concentration-dependent manner (0.01-0.19 microM), reduced the number of monocyte binding sites for monomeric IgG up to 80% without altering the affinity of binding. Its precursor, Factor XII, and the low molecular weight fragment of XIIa, lacking most of the heavy chain region, did not reduce the expression of Fc gamma RI. Neither corn trypsin inhibitor (36 microM) nor diisopropylfluorophosphate (3.6 mM) diminished the effect of Factor XIIa on Fc gamma RI, although each completely inhibited the coagulant and amidolytic activity contained on the light chain of Factor XIIa. Protein synthesis was not a requirement for this effect of Factor XIIa, nor was internalization of Fc gamma RI necessary. In contrast to similar concentrations of IgG, Factor XIIa failed to displace significantly monomeric IgG from the monocyte surface, suggesting that Factor XIIa does not directly compete for Fc gamma RI. The data suggest that the heavy chain of XIIa, which contains domains that may have cell hormone activity, also contains a domain that regulates Fc gamma RI on monocytes. In addition to other hormones and mediators, Factor XIIa may serve a regulatory function in modulating Fc gamma receptor expression during inflammation.

Modulation of human polymorphonuclear leukocyte IgG Fc receptors and Fc receptor-mediated functions by IFN-gamma and glucocorticoids.

Human polymorphonuclear neutrophils (PMN) normally express two distinct types of IgG Fc gamma R, the 40-kDa Fc gamma R referred to as Fc gamma RII and the low affinity 50- to 70-kDa Fc gamma R designated Fc gamma RIII. A third type of Fc gamma R, the 72-kDa high affinity receptor known as Fc gamma RI, is also detectable on PMN that have been activated by IFN-gamma. Using mAb that discriminate among the three known types of Fc gamma R, we examined the effects of IFN-gamma and glucocorticoids on human PMN Fc gamma R expression. We also studied effects of IFN-gamma and the synthetic glucocorticoid dexamethasone (DEX) on antibody-dependent cytotoxicity (ADCC) of chicken erythrocytes and phagocytosis of IgG-coated ox RBC by human PMN. In 20 donors studied, we found that treatment of PMN with 400 U/ml IFN-gamma induced a 9- to 20-fold increase in the number of Fc gamma RI sites per cell, and DEX inhibited this induction of Fc gamma RI by 39 to 73%. Similarly, DEX significantly reduced the IFN-gamma stimulation of ADCC and phagocytosis. IFN-gamma had no effect on expression of Fc gamma RII or Fc gamma RIII. Fc gamma RI and Fc gamma RII expression was unaltered by 24 h of treatment with DEX alone, but Fc gamma RIII expression was sometimes increased by about 20% on PMN cultured with DEX. Nevertheless, we found a small but significant inhibition of ADCC and phagocytosis by 200 nM DEX. Our results indicate that Fc gamma RI plays a major but not exclusive role in the regulation of ADCC and phagocytosis by IFN-gamma and DEX.