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PubMed2003

Changes in monocytic expression of aminopeptidase N/CD13 after major trauma.

HLA-DR expression on monocytes as marker for monocytic function is severely depressed after major trauma. The membrane enzyme aminopeptidase N/CD13 can trigger help in antigen processing by MHC class II molecules of antigen-presenting cells. We determined the simultaneous expression of HLA-DR and CD13 on peripheral blood monocytes of patients with major trauma (injury severity score of > or =16). 1 : 1 conjugates of phycoerythrin (PE)-to-monoclonal antibody were used in combination with QuantiBRITE PE beads for a standardized quantification in terms of antibodies bound per cell (ABC). The very low expression of HLA-DR antigen on monocytes of patients at day 1 after major trauma confirmed previous results in the literature. Monocytic HLA-DR expression increased slowly to reach values in the lower range of healthy volunteers at day 14. Monocytic CD13 expression at day 1 showed values in the range of healthy volunteers, and a strong rise afterwards. Fourteen days after trauma, the monocytic expression of CD13 was still much higher than in the control group. Because lipopolysaccharide (LPS) and the anti-inflammatory cytokine interleukin (IL)-10 have been shown to be involved in the depressed HLA-DR expression on monocytes in trauma patients, we studied the in vitro effects of LPS and interleukin (IL)-10 on the expression of CD13 on monocytes prepared from the peripheral blood of healthy volunteers. Whereas a 3-day IL-10 treatment resulted in a down-regulation of both HLA-DR and CD13 expression on monocytes, LPS caused a down-regulation of HLA-DR but a rapid up-regulation of CD13 levels. Therefore we suggest that, with respect to monocytic CD13 expression, LPS rather than IL-10 could well be the explanation for monocytic surface molecules after severe injury, although other mediators with a CD13 regulating function have to be considered.

Adult↗

PubMed2005

Differential signaling mechanisms regulate expression of CC chemokine receptor-2 during monocyte maturation.

BACKGROUND: Peripheral blood monocytes and monocyte-derived macrophages are key regulatory components in many chronic inflammatory pathologies of the vasculature including the formation of atherosclerotic lesions. However, the molecular and biochemical events underlying monocyte maturation are not fully understood. METHODS: We have used freshly isolated human monocytes and the model human monocyte cell line, THP-1, to investigate changes in the expression of a panel of monocyte and macrophage markers during monocyte differentiation. We have examined these changes by RT-PCR and FACS analysis. Furthermore, we cloned the CCR2 promoter and analyzed specific changes in transcriptional activation of CCR2 during monocyte maturation. RESULTS: The CC chemokine receptor 2 (CCR2) is rapidly downregulated as monocytes move down the macrophage differentiation pathway while other related chemokine receptors are not. Using a variety of biochemical and transcriptional analyses in the human THP-1 monocyte model system, we show that both monocytes and THP-1 cells express high levels of CCR2, whereas THP-1 derived macrophages fail to express detectable CCR2 mRNA or protein. We further demonstrate that multiple signaling pathways activated by IFN-gamma and M-CSF, or by protein kinase C and cytoplasmic calcium can mediate the downregulation of CCR2 but not CCR1. CONCLUSION: During monocyte-to-macrophage differentiation CCR2, but not CCR1, is downregulated and this regulation occurs at the level of transcription through upstream 5' regulatory elements.

Journal Article↗

PubMed1998

Contribution of CD11a/CD18, CD11b/CD18, ICAM-1 (CD54) and -2 (CD102) to human monocyte migration through endothelium and connective tissue fibroblast barriers.

Recently we reported that monocyte migration through a barrier of human synovial fibroblasts (HSF) is mediated by the CD11/CD18 (beta2) integrins, and the beta1 integrins VLA-4 and VLA-5 on monocytes. Here we investigated in parallel the role of beta2 integrin family members, LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) on monocytes, and the immunoglobulin supergene family members, ICAM-1 and ICAM-2 on HSF and on human umbilical vein endothelial cells (HUVEC), in monocyte migration through HSF and HUVEC monolayers. Using function blocking monoclonal antibodies (mAb), when both VLA-4 and VLA-5 on monocytes were blocked, treatment of monocytes with mAb to both LFA-1 and to Mac-1 completely inhibited monocyte migration across HSF barriers, although blocking either of these beta2 integrins alone had no effect on migration, even when VLA-4 and VLA-5 were blocked. This indicates that optimal beta2 integrin-dependent monocyte migration in synovial connective tissue may be mediated by either LFA-1 or Mac-1. Both ICAM-1 and ICAM-2 were constitutively expressed on HSF and on HUVEC, although ICAM-2 was only minimally expressed on HSF. Based on results of mAb blockade, ICAM-1 appeared to be the major ligand for LFA-1-dependent migration through the HSF. In contrast, both ICAM-1 and ICAM-2 mediated LFA-1-dependent monocyte migration through HUVEC. However, neither ICAM-1 nor ICAM-2 was required for Mac-1 -dependent monocyte migration through either cell barrier, indicating that Mac-1 can utilize ligands distinct from ICAM-1 and ICAM-2 on HSF and on HUVEC during monocyte transmigration.

Antigens, CD↗

PubMed1989

Expression and regulation of the HLA-DR antigen on circulating monocytes isolated from patients with rheumatoid arthritis.

Using a modified radioimmunoassay, surface labeling of HLA-DR antigens on monocytes revealed reduced densities in patients with active rheumatoid arthritis (RA) (P less than 0.001) and in gold-treated patients (P less than 0.01) versus normal controls. Significant enhancement of DR antigen expression (P = 0.01), with values similar to those of normal monocytes, occurred in patient monocytes preincubated at 37 degrees C overnight, but not in monocytes preincubated at 4 degrees C. This suggested that a temperature-dependent metabolic process is required to enhance antigen expression. The addition of cycloheximide totally inhibited the enhancement of DR antigen density. Incubation of monocytes with exogenous prostaglandin E2 (10(-5)M final concentration) caused a reduction of DR densities on control and on RA monocytes, although this decrease was more marked in the controls. Addition of indomethacin did not affect DR antigen levels on control monocytes, but greatly enhanced the expression of DR antigens on RA monocytes. When HLA-DR antigen levels were estimated in detergent-solubilized membrane preparations, monocytes from patients with active RA demonstrated normal-to-increased densities compared with control monocytes. Thus, although RA monocytes possess a normal ability to synthesize DR molecules, surface expression of these molecules is inhibited; this inhibition may be mediated by prostaglandin E2 acting as a negative suppressive signal.

Arthritis, Rheumatoid↗

PubMed1990

Formation of multinucleated cells with osteoclast precursor features in human cord monocytes cultures.

A common lineage between monocytes and osteoclasts has been suggested but not yet proved, and an osteoclast precursor might be an immature cell of the monocyte-macrophage family. We therefore compared the ability of cord blood and adult monocytes in long-term culture to differentiate toward osteoclasts. Both adult and cord monocytes were cultured for 3 weeks in the presence of 20% horse serum. The proportion of multinucleated cells formed was influenced by 1,25(OH)2D3 in cord, but not in adult monocyte cultures: 10(-9)M 1,25(OH)2D3 increased multinucleated cells from 13 +/- 2 to 26 +/- 1% of total cells in cord monocyte cultures. The formation of multinucleated cells in cord monocyte cultures, in the presence of 10(-9) M 1,25(OH)2D, was decreased by salmon calcitonin (dose dependently from 10(-8) to 10(-6) M) and increased by 1-34 parathormone (100 ng/ml). None of these hormones induced any modification of the proportion of multinucleated cells formed in adult monocytes culture. Specific antigens on the membrane of the cells obtained after 3 weeks culture in the presence of 10(-9) M 1,25(OH)2D3 were assessed by immunocytochemistry. The respective proportion of adult and cord labeled cells was 64 +/- 11 vs. 63 +/- 6% with Leu M5 (specific for monocyte) and 68 +/- 7 vs. 30 +/- 10% (P less than 0.05) with the anti-HLA DR antibody. The monoclonal antibody 23C6 is specific to the vitronectin receptor, which is highly expressed by osteoclasts--41 +/- 2% of the cells in cord monocyte cultures--but none in the adult monocytes culture were labeled with 23C6 at the end of the culture period.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitonin↗

PubMedDate not supplied

Glucose and glutamine utilization by rat lymphocytes, monocytes and neutrophils in culture: a comparative study.

Glucose and glutamine utilization and production of glutamate and lactate were determined for up to 48 h in lymphocytes, monocytes and neutrophils cultured in medium rich in metabolites and vitamins. Glucose was utilized by the three cell types in culture in the following order: neutrophils > monocytes > lymphocytes, whereas lactate was produced in the order: monocytes > neutrophils > lymphocytes. The consumption of glucose followed the activity of glucose-6-phosphate dehydrogenase but it was not related to hexokinase activity. Glutamine was consumed by the three leukocyte types in culture as follows: neutrophils > lymphocytes > or = monocytes. The consumption of glutamine was not fully related to the activity of phosphate-dependent glutaminase. The production of glutamate was not remarkably different among the three cell types. For comparison, glutamine and glucose utilization and glutamate and lactate production were also evaluated using 1-h incubated leukocytes. Under this condition, only glucose or glutamine was added to the medium. Glucose was utilized as follows: neutrophils > monocytes > lymphocytes, whereas lactate was produced in the following order: monocytes > or = neutrophils > lymphocytes. Glutamine was consumed as follows: neutrophils > lymphocytes > monocytes, whereas glutamate was produced as follows: neutrophils > or = monocytes = lymphocytes. The ratio of the amount of glucose/glutamine consumed by 1-h incubated cells was 0.5 for neutrophils, 1.5 for monocytes, and 0.3 for lymphocytes. However, the three cell types cultured for 48 h utilized glucose to a much higher degree than glutamine. The ratio of the amount of glucose/glutamine utilized by the cultured cells was 8.9 for neutrophils, 16.4 for monocytes, and 6.7 for lymphocytes. These observations support the proposition that glutamine is required in much higher amounts than glucose to accomplish the total metabolic requirement of leukocytes. Under conditions closer to physiological when the availability of a variety of metabolites and vitamins is not restricted, glucose is the preferred substrate for lymphocytes, monocytes and neutrophils.

Animals↗

PubMed1980

Use of carbon labeling to demonstrate the role of blood monocytes as precursors of the 'ameboid cells' present in the corpus callosum of postnatal rats.

Cells with features suggestive of ameboid motion and phagocytic properties are observed in the rat corpus callosum during the first few days of life. These cells, hereafter referred to as 'ameboid cells', have been investigated in several ways. An electron microscopic study of the corpus callosum in 5- to 7-day-old rats indicated that most 'ameboid cells' were typical macrophages, but some displayed features of monocytes, while others appeared to be transitional between the two types. These observations raised the possibility that blood monocytes were the precursors of 'ameboid cells'. This possibility was tested by injecting a suspension of carbon particles into the circulation of rats of various ages to label and trace monocytes. Within 15 minutes after injection, carbon particles were seen between cells in blood smears as well as in the lumen of capillaries, but not between cells and axons in corpus callosum. By a half hour, a few of the circulationg monocytes, and with time, up to half of them, contained carbon particles. Five days after injection, carbon particles were observed in cells of the corpus callosum identified as 'ameboid cells' of the monocytic and macrophagic type. Such carbon-containing cells were seen in many of the animals injected at the age of 0-1 day, in few of those injected at 3-5 days, and in none of the older animals. Since free carbon had not been observed in corpus callosum spaces, it was concluded that 'ameboid cells' did not pick up carbon locally. The alternative was that blood monocytes, after ingesting carbon particles in the circulation, migrated to the corpus callosum and settled as 'ameboid cells'. In the hope of obtaining a direct confirmation of this conclusion, blood cells obtained from carbon-injected Lewis rats were centrifuged in a Percoll gradient to obtain a fraction which contained 70-80% monocytes, less than 2% granulocytes, and 20-30% lymphocytes. Carbon was present in up to half of the monocytes and 1% of the granulocytes, but not in the lymphocytes; and it was calculated that over 99% of the carbon-labeled cells were monocytes. The cell fraction was then introduced into the blood circulation of 2- to 3-day-old syngeneic Lewis rats, and the animals were sacrificed 5 days later. Occasional carbon-labeled cells appeared not only in liver, spleen and connective tissue, but also in the corpus callosum, where they were identified as 'ameboid cells' of the monocytic and macrophagic type. Even though such cells were infrequent, their presence conclusively demonstrated that at least some 'ameboid cells' of the corpus callosum were derived from circulating blood monocytes.

Age Factors↗

PubMed1987

Interferon-gamma restores T lymphocyte proliferation of nonresponders to IgG1 anti-CD3 via the induction of Fc gamma 1 receptors on monocytes.

Human peripheral blood T lymphocytes are stimulated to grow and divide by some mouse anti-CD3 monoclonal antibodies. This polyclonal mitogenesis is dependent on both their immunoglobulin subclass and the presence of monocytes. The unresponsiveness of T lymphocytes from certain individuals to mouse IgG1 (or IgG2a) antibodies is due to a failure of their monocytes to bind these IgG isotypes. In this study, we have selected such nonresponder subjects to IgG1 anti-CD3 (UCHT 1) in order to study their monocytes. Two assays were used: IgG1 and IgG2 EA rosettes to evaluate their Fc receptor-binding capacity, and IgG-mediated monocyte chemiluminescence to test their receptor-related activation since mouse anti-T cell antibodies binding to lymphocytes trigger monocyte chemiluminescence via their Fc receptor. We have observed that in all nonresponder subjects the absence of IgG1 anti-CD3 monocyte chemiluminescence strictly correlates with the absence of IgG1 EA rosettes. Thus, the failure to respond to UCHT 1, in all nonresponders tested to date, is due to the absence of Fc gamma 1 receptors on their monocytes. Treatment of nonresponder monocytes by recombinant interferon-gamma was shown to restore T cell proliferation and monocyte chemiluminescence in nonresponders. This effect of interferon-gamma correlates with the appearance of Fc gamma 1 receptors on monocytes from these individuals. This work strongly suggests that nonresponder monocytes possess functional genes for Fc gamma 1 receptors which are not expressed normally at a detectable level but can be induced by interferon-gamma.

Antibodies, Monoclonal↗

PubMed1991

Platelet-induced expression of Fc gamma RIII (CD16) on human monocytes.

Monocytes constitutively express Fc receptor (FcR) for IgG type I (CD64) and type II (CD32), but not type III (CD16). Prior studies have indicated that in vitro culture of monocytes results in spontaneous induction of CD16, but this phenomenon has been variable and the mechanism unexplained. Here, we demonstrate that activated platelets are responsible for induction of CD16 on monocytes, as a consequence of TGF-beta release. Local release of TGF-beta by activated platelets at sites of tissue damage may induce CD16 on infiltrating or resident monocytes that in turn facilitate the function of these effector cells. The FcR on these CD16+ monocytes is functionally competent, and enables the monocytes to kill murine anti-CD16 hybridoma cells. CD16 expressed on platelet-activated monocytes is structurally similar to the transmembrane-anchored CD16-II polypeptide expressed on natural killer (NK) cells. However, whereas CD16-II on NK cells is co-associated with CD3 zeta, we were unable to detect CD3 zeta transcript or protein in monocytes. Transcripts for the gamma subunit of the high-affinity IgE FcR (Fc epsilon RI-gamma) were detected in monocytes, and presumably gamma proteins are co-associated with CD16-II in these cells. Nucleotide sequence analysis of Fc epsilon RI-gamma cDNA derived from both NK cells and cultured monocytes indicated identity with the structure previously cloned from basophils. Since CD16+ monocytes can kill anti-CD16 hybridoma cell targets in the absence of CD3 zeta, these results indicate that CD3 zeta is not essential for signal transduction in CD16-II-mediated cytotoxicity.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1991

Dissociation between plasma and monocyte-associated cytokines during sepsis.

We report our investigations of circulating interleukin (IL) 1 beta, IL 6 and tumor necrosis factor (TNF)-alpha, as well as cell-associated IL 1 alpha, IL 1 beta and TNF-alpha in plasma and monocytes of 21 patients with sepsis syndrome and 6 patients with non-septic shock. Longitudinal studies reveal that (a) the most frequent detectable plasma cytokines were TNF-alpha and IL 6, (b) the presence and the kinetics of circulating cytokines were independent of one other, (c) detectable levels of cytokines could be found for a long period of time, and (d) significantly higher levels of IL 6 were found for non-surviving patients. Because of the in vivo half-life of cytokines and of the existence of numerous specific high-affinity receptors, it is quite probable that detectable plasma cytokines represent the excess of produced mediators which have not been trapped by the target cells. TNF-alpha (410 +/- 65 pg/10(6) monocytes) and IL 1 beta (153 +/- 60 pg/10(6) monocytes) were frequently found associated to monocyte lysates (88% and 50%, respectively). Despite the fact that IL 1 alpha is the most abundant cytokine found associated to monocytes following in vitro activation, IL 1 alpha was rarely found in monocytes of intensive care unit patients (29%). No correlation was found to exist between the levels of plasma cytokines and cell-associated cytokines. Some patients had plasma TNF-alpha or IL 1 beta in the absence of the corresponding monocyte-associated cytokine. This observation suggests that cells other than monocytes can participate in the production of circulating cytokines. At the end of the longitudinal study (day 14 +/- 2), only 2/12 surviving patients still had plasma TNF-alpha, whereas 8/12 had monocyte-associated TNF-alpha. These results indicate that activation of monocytes still occurs in patients for whom no plasma cytokines can be detected. Thus, in addition to the measurement of plasma cytokine, measurement of cell-associated cytokine appears useful to assess cytokine production and monocyte activation in vivo.

Bacterial Infections↗

PubMed1995

Monocyte activation: rapid induction of alpha 1/beta 1 (VLA-1) integrin expression by lipopolysaccharide and interferon-gamma.

Monocytes play a key role in inflammation, tissue injury and remodelling and wound healing, and most monocyte effector functions are dependent on adhesive interactions. We have analyzed the changes in the pattern of beta 1 integrin expression that take place during monocyte activation and demonstrated that lipopolysaccharide (LPS) and interferon (IFN)-gamma specifically induce the expression of the alpha 1/beta 1 integrin, which was detectable on the monocyte membrane as early as 12 h after monocyte activation. The up-regulated alpha 1/beta 1 expression was not dependent on monocyte adherence to solid surfaces, and Northern blot analysis revealed that LPS and IFN-gamma induce the alpha 1 mRNA de novo. Monocyte deactivating cytokines such as interleukin (IL)-4 or IL-10, could only minimally inhibit the LPS- or IFN-gamma mediated up-regulation of alpha 1/beta 1, suggesting that cytokine release subsequent to monocyte activation does not play a major role in the integrin induction. Interestingly, the LPS-induced expression of alpha 1/beta 1 was found to be dependent on the redox state of the cell, since it was inhibited by antioxidants which also altered the morphological changes that take place during monocyte culture in vitro. The rapid induction of alpha 1 in LPS-activated monocytes suggests that alpha 1/beta 1 might be involved not only in monocyte/extracellular matrix interactions during inflammatory reactions, but also in contributing to further monocyte activation and cytokine production during septic shock syndrome.

Cell Adhesion↗

PubMed1997

An Fc gamma receptor I (CD64)-negative subpopulation of human peripheral blood monocytes is resistant to killing by antigen-activated CD4-positive cytotoxic T cells.

It has been demonstrated that in monocyte/T cell co-cultures activated with recall antigens, cytotoxic T cells were generated which are able to reduce the number of antigen-presenting monocytes. In previous studies we could show that a minor subset of monocytes, the Fc gamma receptor I-negative (CD64-) monocytes, exhibits significantly higher antigen-presenting capacity than the main population of monocytes (> 90%) which are Fc gamma receptor I-positive (CD64+). Therefore, we addressed the question whether they are also differentially susceptible to T cell-mediated killing. In the present study we demonstrate that the CD64- monocyte subset is more resistant to killing by antigen-activated T cells than CD64+ monocytes, as indicated by a higher viability and recovery of CD64- monocytes. This mechanism involves CD95 (Fas) antigen, since monocyte death in co-cultures with antigen-activated T cells could be partially reduced by blocking anti-Fas monoclonal antibodies (mAb). In agreement with this finding, although CD95 antigen was expressed on CD64+ and CD64- monocytes at comparable levels, killing of CD64- monocytes by activating anti-Fas mAb was lower than of CD64+ monocytes.

CD4-Positive T-Lymphocytes↗

PubMed1994

Mechanism of cigarette smoke condensate induced adhesion of human monocytes to cultured endothelial cells.

Cigarette smoking is ranked among the leading risk factors in the etiology of atherosclerotic vascular disease. The mechanisms, however, that link cigarette smoking to increased incidence of atherosclerosis are not understood. The adherence of circulating monocytes to the endothelium, migration into the subendothelium, and subsequent formation of foam cells are principal initial events in the development of atherosclerosis. We therefore determined whether cigarette smoke caused increased adherence of monocytes to endothelial cells and the cellular mechanism of this increased adherence. Cigarette smoke condensate (CSC), the particulate fraction of cigarette smoke derived from 2R1 standard research cigarettes, at a concentration of 25-30 micrograms/ml (average yield of CSC is 26.1 mg/cigarette), augmented (70-90%) basal adherence of human peripheral blood monocytes to a cultured monolayer of endothelial cells derived from bovine aorta (BAEC) and human umbilical vein (HUVEC). There was a concomitant increase in the expression of CD11b ligand on the surface of monocytes as determined by flow cytometry, utilizing FITC conjugated Mab MO-1 (CD11b). However, nicotine (1-15 micrograms/ml) and cadmium sulfate (10 micrograms/ml), constituents of CSC, individually or in combination had no effect either on CD11b expression or adherence of monocytes to endothelial cells. Treatment of HUVEC with CSC for 60 min also resulted in an increased expression of ICAM-1 and ELAM-1 as determined by mean fluorescence intensity of ICAM-1 and ELAM-1 labeled cells in flow cytometric analysis. The CSC induced expression of CD11b in monocytes was optimal at 25-30 min and was inhibited by protein kinase C inhibitors, staurosporine and H-7, and also by baicalein, a lipoxygenase inhibitor. Similarly, CSC induced ICAM-1 and ELAM-1 expression in HUVEC was inhibited by protein kinase C inhibitors. CSC stimulated the adherence of human monocytes but not the monocytic cell lines HL-60, U937, and THP-1 to endothelial cells. The CSC stimulated adherence of human monocytes was inhibited (80%) by MAb to CD11b and 50% by Mab to ICAM-1 and ELAM-1. These results suggest that cigarette smoke particulate constituents activate protein kinase C, leading to increased surface expression of adhesive ligand CD11b on peripheral blood monocytes and counter receptor(s) ICAM-1 and ELAM-1 in endothelial cells. The expression of ligand and counter receptor leads to potentiated adherence of monocytes to endothelial cells, an initial event in the pathogenesis of cigarette smoke induced inflammatory response in the vessel wall.

Alkaloids↗

PubMed1986

Differences in Fc receptor expression between small and large guinea pig monocytes.

Guinea pig monocytes have been separated into subpopulations differing in size, morphology, and cytochemistry. We report now that these peripheral blood monocyte subpopulations differ also in native Fc receptor expression. All freshly isolated small monocytes formed Fc rosettes with sensitized sheep erythrocytes, whereas Fc receptor expression was not detectable on large monocytes. However, Fc receptor expression developed rapidly in culture such that by 48 hours all monocytes were positive. This phenomenon was inhibited by 2-deoxy-D-glucose and cycloheximide, suggesting that Fc receptor expression depended upon glycolysis and protein synthesis. Large monocytes participated in antibody-dependent lysis of sheep erythrocyte targets. That large monocytes lacking Fc receptors were cytolytic in this assay was concordant with expression of Fc receptors during the 16-hour test period. We believe that the large number of lymphocytes present in the Fc receptor-positive small monocyte fraction interfered with their measurement of antibody-dependent cytotoxicity. We conclude that Fc receptor expression on guinea pig monocytes is heterogeneous within the peripheral circulation. These differences quickly diminish in vitro with the expression of Fc receptors by all monocytes. Additionally, antibody-dependent lysis of sensitized erythrocytes by guinea pig mononuclear cells is due to monocytes and not lymphocytes or Kurloff cells.

Animals↗

PubMed1995

IL-10 up-regulates human monocyte phagocytosis in the presence of IL-4 and IFN-gamma.

Interleukin-10 (IL-10), a cytokine produced by type 2 helper T (Th2) cells, inhibits the microbicidal effector function of interferon-gamma (IFN-gamma)-activated macrophages. However, recent observations indicate that IL-10, like IFN-gamma, increases Fc gamma RI expression and Fc gamma R-mediated cytotoxic activity on human monocytes, suggesting that this cytokine cannot be classified purely as a monocyte deactivator. The present study found that incubation for 40 h of human monocytes or monocyte-derived macrophages in the presence of IL-10 caused a significant enhancement of their capacity to ingest particles coated with immunoglobulin G (Fc gamma R-mediated ingestion) or with C3b/C3bi fragments of the complement system (CR1/CR3-mediated ingestion). The number of phagocytosing cells (% phagocytosis) and the number of ingested particles per cell (phagocytic index) were both significantly higher after 40-h incubation of monocytes with IL-10 concentrations > or = 1 U/ml. This up-regulating activity on phagocytosis was completely reversed by anti-IL-10 monoclonal antibody (mAb). As previously reported, IL-10 stimulated Fc gamma RI expression on monocytes but did not induce the expression of Fc gamma RII, Fc gamma RIII, CR1, and CR3. IFN-gamma, like IL-10, up-regulated only Fc gamma RI expression but significantly reduced both Fc gamma R- and CR-mediated ingestion. IL-10 almost completely reversed the IFN-gamma-induced inhibition of both Fc gamma R- and CR-mediated phagocytosis, without concomitant changes in membrane expression of phagocytic receptors. Exposure of monocytes to IL-4 reduced the membrane expression of all three Fc gamma Rs and also inhibited Fc gamma R-mediated ingestion. On the other hand, IL-4 up-regulated both CR3 expression and CR-mediated ingestion on cultured monocytes. IL-10 not only neutralized the down-regulatory effect of IL-4 on Fc gamma R expression but also completely reversed the IL-4-induced suppression of Fc gamma R-mediated phagocytosis. Exposure of monocytes to a combination of IL-10 and IL-4 resulted in a synergistic effect on CR-mediated ingestion, even though no additive effects were observed on CR membrane expression. Finally, culture of monocytes in medium containing anti-IL-10 mAb significantly reduced their capacity to ingest IgG- or C3b/C3bi-coated particles, suggesting a role for endogenously produced IL-10 in the modulation of phagocytosis by human monocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗

PubMed2005

Enhanced monocyte binding to human cytomegalovirus-infected syncytiotrophoblast results in increased apoptosis via the release of tumour necrosis factor alpha.

We have shown that monocytes bound to intercellular adhesion molecules (ICAM-1) on syncytialized placental trophoblasts (ST) induce trophoblast apoptosis, and that ST infection by human cytomegalovirus (HCMV) up-regulates ICAM-1. We hypothesize that the focal loss of trophoblast seen in HCMV-infected placenta is mediated by increased adherence of monocytes at sites of infection. We find that ST cultures (differentiated from primary cytotrophoblasts) increase monocyte binding when infected with HCMV. Monocyte adhesion was inhibited by antibodies to ICAM-1 and its ligand leukocyte function-associated molecule (LFA-1) on monocytes. When co-cultured with adhering monocytes, infected ST cultures had higher levels of apoptosis than infected cultures alone. Although trophoblast apoptosis clustered around adhering monocytes, it occurred only in non-infected cells. Blocking monocyte binding with ICAM-1 and LFA-1 antibodies reduced the rate of apoptosis to that of the infected culture. Co-cultures incubated with TNFalpha antibody and EGF inhibited both monocyte- and HCMV-induced apoptosis but did not block binding. We conclude that HCMV stimulates ST culture expression of ICAM-1, which binds to LFA-1 on monocytes that release TNFalpha, thereby inducing apoptosis of neighbouring uninfected trophoblasts. The above data indicates that trophoblast loss associated with HCMV infection can be caused by increased monocyte adhesion to ST.

Apoptosis↗

PubMed1993

Effect of T cells on the complement production by monocytes.

We studied the role of T cells in the regulation of C3 or C4 production by monocytes. While cocultured T cells reduced C3 production, they enhanced C4 production by monocytes in a number-dependent manner. Interleukin-2 enhanced these effects of T cells on C3 and C4 production, indicating that activated T cells had greater effects on complement production by monocytes. CD4+ T cells had greater effects than those of CD8+ T cells on the C3 or C4 production by monocytes, indicating that CD4+ T cells were mainly involved in the regulation of C3 and C4 production by monocytes. T-cell-conditioned medium (T-CM) also decreased C3 and enhanced C4 production, but the effect of T-CM on C3 and C4 production was less remarkable than that of T cells. T cells separated by transwell inserts from monocytes had similar effects as those of T-CM on complement production. Anti-IFN-gamma antibody completely blocked the suppressing effect on C3 production and partially blocked the stimulating effect of T cells on C4 production. These results indicate that T cells regulate C3 or C4 production by monocytes via IFN-gamma as a humoral factor. Moreover, the stimulating effect of T cells on C4 production was partially blocked when monocytes and T cells were incubated with anti-CD2, anti-LFA-1, and anti-HLA-DR antibodies, and anti-CD2 partially blocked the suppressing effect of T cells on C3 production by monocytes. These results indicate that T cells modulate the C3 and C4 production by monocytes not only via a humoral factor but also via a direct interaction with monocytes.

Cell Communication↗

PubMed2001

Involvement of ADAM9 in multinucleated giant cell formation of blood monocytes.

Monocytes-macrophages are converted to multinucleated giant cells by stimulation with various cytokines, and osteoclasts are the multinucleated giant cells derived from a monocyte-macrophage lineage. However, at present, the fusion peptides have not been clearly identified in monocytes-macrophages. The ADAM are a family of transmembrane glycoproteins that have a role in various biological functions. Interestingly, fertilin-alpha, ADAM9, and ADAM11 have potential fusion peptides. In this study, which ADAM was specifically expressed in monocytes stimulated with anti-CD98 antibody or RANKL and which factor(s) was functioning in monocytes as a fusion protein were investigated. ADAM1, 8, 10, 12, 15, 17, 20, and 21 mRNAs are expressed in blood monocytes incubated with control antibody, anti-FRP-1/CD98 antibody, or RANKL + M-CSF, while ADAM2, 7, 11, 13, 19, 23, 29, and 30 mRNAs could not be detected in these blood monocytes. Expression of ADAM9 and ADAM10 mRNAs are enhanced by either RANKL + M-CSF or anti-CD98 antibody. The expression of ADAM9 and ADAM10 is also induced in blood monocytes by anti-CD98 mAb. An anti-ADAM9 antibody enhances CD98-mediated cell aggregation, while it blocks CD98-mediated and RANKL-mediated multinucleated giant cell formation. A hydroxamate-based metalloprotease inhibitor, SI-27, which is found to suppress ADAM9 activity, suppresses multinucleated giant cell formation. New protein synthesis is necessary for the expression of ADAM9 mRNA and genistein suppresses induction of ADAM9 mRNA. This is the first report that ADAM9 is involved in monocyte fusion, such as CD98-mediated and RANKL-mediated cell fusion of blood monocytes. Furthermore, AMAM9 is one candidate for a fusion peptide in blood monocytes.

ADAM Proteins↗