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PubMed1992

Decreased monocyte-mediated angiogenesis in scleroderma.

Scleroderma is a disease characterized by proliferative vascular lesions in which monocytes/macrophages may play a key role. Monocytes were isolated from 14 scleroderma patients and 11 normal controls and cultured with or without lipopolysaccharide (LPS) (5 micrograms/ml). Monocyte-conditioned medium was assayed in the rat corneal bioassay for angiogenesis. Conditioned medium from normal monocytes was nonangiogenic, as was conditioned medium from scleroderma monocytes. While conditioned medium from LPS-activated normal monocytes was potently angiogenic in 11/13 corneas, conditioned medium from LPS-activated scleroderma monocytes was angiogenic in only 3/14 corneas. Levels of the angiogenic cytokine tumor necrosis factor-alpha (TNF-alpha) were measured in conditioned medium from scleroderma and normal monocytes. TNF-alpha levels were not significantly different in patient and control groups and thus do not account for the decreased angiogenic activity exhibited by scleroderma monocytes. As monocytes require activation to produce angiogenic activity, we determined the cell surface binding of monoclonal antibodies to activation-related (HLA-DR, 3D8, and 8D7) and other (Leu-M5) markers on monocytes by radioimmunoassay. Monocytes were cultured alone, with LPS (5 micrograms/ml), or with interferon-gamma (IFN) (200 units/ml). The usual increase in binding of anti-HLA-DR on stimulation of scleroderma monocytes with IFN was slightly less than that of controls. IFN-stimulated monocytes bound less anti-8D7 than controls. Anti-3D8 and anti-Leu-M5 binding was comparable in both groups. These results suggest that scleroderma monocytes do not produce normal levels of angiogenic activity with LPS stimulation, have some altered markers of activation on their cell surfaces, and may thus contribute to the aberrant vascular proliferation found in this disease.

Adult↗
PubMed1988

IgG-, IgA-, and IgE-induced release of leukotriene C4 by monocytes isolated from patients with atopic dermatitis.

Purified peripheral blood monocytes isolated from patients with atopic dermatitis (AD) and from nonallergic normal donors were compared for their abilities to release leukotriene C4 (LTC4), leukotriene B4 (LTB4) and beta-glucuronidase in response to challenge with aggregated immunoglobulins or anti-immunoglobulins. The relationship between mediator release and the number of monocytes that formed rosettes with immunoglobulin-coated indicator cells was examined. Patients with AD had twice as many IgA- and three times as many IgE-rosetting monocytes as normal donors (48 +/- 12% versus 27 +/- 10% and 40 +/- 15% versus 14 +/- 3%, respectively), and yet the amounts of IgA- and IgE-induced LTC4 released were similar for both groups. This apparent discrepancy did not result from a decreased capacity for arachidonate metabolism via the C5-lipoxygenase pathway, since stimulation of monocytes from patients and normal donors with the calcium ionophore A23187 induced similar amounts of LTC4 and LTB4 release (LTC4, 3.0 +/- 1.7 versus 3.0 +/- 1.0 ng/10(6) cells; LTB4, 5.3 +/- 0.7 versus 5.2 +/- 0.5 ng/10(6) cells, respectively). In addition, aggregated IgG-induced LTC4 release by monocytes of both groups was similar, concomitant with an equivalent number of IgG-rosetting cells. Determination of cytophilically bound IgG and IgE by flow cytometry demonstrated that monocytes from atopic patients had more IgG bound than monocytes from normal donors. Similar amounts of IgE were detected on most monocytes from both groups, despite the higher serum IgE levels of patients. However, approximately 3% to 8% of monocytes from atopic but not normal donors stained brightly for IgE, suggesting that relatively large amounts of cytophilic IgE were bound to a small percentage of the patients' monocytes. Challenge of monocytes with anti-IgE or anti-IgG induced release of similar amounts of LTC4 for both groups, despite the presence of more cytophilic IgG on monocytes from atopic donors. These data indicate that monocytes from patients with AD release LTC4 and LTB4 in response to challenge with aggregated IgE or anti-IgE, as well as aggregated IgG, IgA, and anti-IgG. However, under our in vitro conditions, stimulation of patients' monocytes with aggregated IgA or IgE was not associated with increased mediator release, despite higher percentages of IgA- and IgE-rosetting cells compared to normal donors.

Antigens, Differentiation↗
PubMed1993

Role of dialysis modality in responses of blood monocytes and peritoneal macrophages to endotoxin stimulation.

Constitutive and endotoxin (lipopolysaccharide [LPS])-stimulated release of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and prostaglandin E2 (PGE2) by blood monocytes and peritoneal cell preparations from patients on various forms of dialysis was measured. Monocytes were obtained from healthy controls (n = 20), and from patients on peritoneal dialysis (n = 8), on hemodialysis with cellulose ester membranes (n = 9), and on hemodialysis with polysulfone membranes (n = 8). Peritoneal macrophages were recovered by lavage during laparoscopic surgery from 11 healthy controls, from dialysate in 37 patients on peritoneal dialysis, and at catheter placement for transfer to peritoneal dialysis from eight patients on hemodialysis with polysulfone membranes. Peak LPS-induced production of TNF-alpha, IL-1 beta, and IL-6 by monocytes from patients on peritoneal dialysis and cellulose ester hemodialysis was less than that by monocytes from healthy controls. In contrast, monocytes from patients treated with polysulfone hemodialysis produced amounts of cytokine not different from controls. Lipopolysaccharide-stimulated PGE2 production by monocytes was the same in both patient and control groups. Peritoneal cell preparations from patients on peritoneal dialysis showed decreased release of IL-1 beta and TNF-alpha as compared with control peritoneal cells and with their own blood monocytes. To determine whether the decreased response to LPS by peritoneal cells compared with their own blood monocytes could be attributed to lower numbers of macrophages in the peritoneal cell preparations, adherence of peritoneal cells to plastic was performed. Adherence increased the percentage of macrophages from 70% to more than 90%. In monocytes and adherence purified peritoneal macrophages from peritoneal dialysis patients, no significant difference between monocytes and adherent peritoneal macrophages could be found for TNF-alpha and PGE2. Interleukin-1 beta production by the adherent peritoneal macrophages, as by total peritoneal cells, was significantly lower than that by monocytes. Constitutive production of PGE2 and IL-6 by peritoneal cells from patients on peritoneal dialysis was significantly increased. In contrast, LPS-stimulated production of TNF-alpha, IL-1 beta, and IL-6 by blood monocytes and peritoneal cells from patients receiving hemodialysis with polysulfone membranes was comparable to that produced by monocytes and peritoneal cells obtained from healthy controls. Thus, blood monocytes and peritoneal cells from patients on peritoneal dialysis and from patients on hemodialysis with cellulose-ester membranes demonstrate a decreased cytokine response to LPS, suggesting a state similar to endotoxin tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2001

Chlamydia pneumoniae-infected monocytes exhibit increased adherence to human aortic endothelial cells.

Interactions between monocytes and endothelial cells play an important role in the pathogenesis of atherosclerosis, and monocyte adhesion to arterial endothelium is one of the earliest events in atherogenesis. Work presented in this study examined human monocyte adherence to primary human aortic endothelial cells following monocyte infection with Chlamydia pneumoniae, an intracellular pathogen associated with atherosclerosis by a variety of sero-epidemiological, pathological and functional studies. Infected monocytes exhibited enhanced adhesion to aortic endothelial cells in a time- and dose-dependent manner. Pre-treatment of C. pneumoniae with heat did not effect the organism's capacity to enhance monocyte adhesion, suggesting that heat-stable chlamydial antigens such as chlamydial lipopolysaccharide (cLPS) mediated monocyte adherence. Indeed, treatment of monocytes with cLPS was sufficient to increase monocyte adherence to endothelial cells, and increased adherence of infected or cLPS-treated monocytes could be inhibited by the LPS antagonist lipid X. Moreover, C. pneumoniae-induced adherence could be inhibited by incubating monocytes with a mAb specific to the human beta 2-integrin chain, suggesting that enhanced adherence resulted from increased expression of these adhesion molecules. These data show that C. pneumoniae can enhance the capacity of monocytes to adhere to primary human aortic endothelial cells. The enhanced adherence exhibited by infected monocytes may increase monocyte residence time in vascular sites with reduced wall shear stress and promote entry of infected cells into lesion-prone locations.

Antibodies, Monoclonal↗
PubMed1997

Inhibition of neutrophil and monocyte recruitment by endogenous and exogenous lipocortin 1.

1. The role played by endogenous lipocortin 1 in the anti-migratory action exerted by dexamethasone (Dex) on monocyte recruitment in an in vivo model of acute inflammation was investigated by use of several neutralizing polyclonal antibodies raised against lipocortin 1 or a lipocortin 1-derived N-terminus peptide (peptide Ac2-26). The efficacy of peptide Ac2-26 in inhibiting monocyte and polymorphonuclear leucocyte (PMN) recruitment was also tested. 2. Intraperitoneal (i.p.) injection of zymosan A (1 mg) produced a time-dependent cell accumulation into mouse peritoneal cavities which followed a typical profile of acute inflammation: PMN influx was maximal at 4 h post-zymosan (between 15 and 20 x 10(6) cells per mouse), and this was followed by an accumulation of monocytes which peaked at the 24 h time-point (between 10 and 15 x 10(6) cells per mouse). 3. Dex administration to mice reduced zymosan-induced 4 h PMN infiltration and 24 h monocyte accumulation with similar efficacy: approximately 50% of inhibition of recruitment of both cell types was achieved at the dose of 30 micrograms per mouse (approximately 1 mg kg-1, subcutaneously (s.c.)). Maximal inhibitions of 64% and 67% on PMN and monocyte recruitment, respectively, were measured after a dose of 100 micrograms per mouse (approximately 3 mg kg-1, s.c.). 4. Dex (30 micrograms s.c.) inhibited monocyte (53%) and PMN (69%) accumulation in response to zymosan application in mice which had been treated with a non-immune sheep serum (50 microliters s.c.). In contrast, the steroid was no longer active in reducing cell accumulation in mice which had been passively immunized against full length human recombinant lipocortin 1 (serum LCS3), or against lipocortin 1 N-terminus peptide. 5. Treatment of mice with vinblastine (1 mg kg-1, intravenously (i.v.)) produced a remarkable leucopenia as assessed 24 h after administration. This was accompanied by a 60% reduction in 4 h-PMN influx, and by a 27% reduction in 24 h-monocyte accumulation, measured after zymosan administration. The inhibitory effect of Dex on monocyte recruitment was not significantly modified in vinblastine-treated mice, with 36% and 57% of inhibition calculated at the dose of 30 micrograms Dex, and 70% and 60% of inhibition at 100 micrograms Dex, in vehicle- and vinblastine-treated mice, respectively. 6. Treatment of mice with peptide Ac2-26 dose-dependently attenuated PMN influx at 4 h post-zymosan with a significant effect at 100 micrograms per mouse (45% of inhibition, n-9, P < 0.05) and a maximal effect of 61% inhibition at the highest dose tested of 200 micrograms s.c. (n = 14, P < 0.05). No effect of peptide Ac2-26 (200 micrograms s.c.) was seen on zymosan-induced 24 h monocyte recruitment. In contrast, administration of 200 micrograms peptide Ac2-26 every 6 h was effective in reducing the number of monocytes harvested from the inflamed peritoneal cavities at 24 h post-zymosan: 9.40 +/- 0.58 x 10(6) monocytes per mouse (n = 13) and 5.74 +/- 0.34 monocytes per mouse (n = 14) in vehicle- and peptide Ac2-26-treated mice, respectively (P < 0.05). 7. Finally, peptide Ac2-26 produced a concentration-dependent inhibition of the rate of phagocytosis of mouse resident peritoneal macrophages as measured by flow cytometry, with a maximal reduction of 34% at the highest concentration tested of 100 micrograms ml-1 (n = 8 experiments performed in duplicate; P < 0.05). 8. In conclusion, this study suggests that in vivo monocyte recruitment during acute inflammation is, at least in part, under the negative modulatory control of endogenous lipocortin 1 (as seen after administration of Dex by using the specific antisera) and exogenous lipocortin 1 mimetics (as observed with peptide Ac2-26. In addition to the neutrophil, we can now propose that the monocyte also can be a target for the in vivo anti-inflammatory action of lipocortin 1.

Animals↗
PubMed2002

Immunological characterization of a gammadelta T-cell stimulatory ligand on autologous monocytes.

Bovine gammadelta T cells are stimulated to proliferate by autologous monocytes. This is referred to as the autologous mixed leucocyte reaction (AMLR). It has been shown previously that the stimulatory component is constitutively expressed on the monocyte plasma membrane and is a protein or has a protein moiety. Here we showed that gammadelta T-cell responses to the monocytes requires interaction with the T-cell receptor because Fab1 fragments of a monoclonal antibody (mAb) that reacts with the delta chain of the T-cell receptor blocked proliferation in the AMLR. Monocyte molecules involved in stimulation were also characterized further by biochemical and immunological methods. A mAb, named M5, was generated by immunizing mice with bovine monocytes and shown to block the ability of monocytes to stimulate in the AMLR. Treatment of monocytes or monocyte membranes with high salt, chelating agents or phospholipase C did not affect their ability to stimulate gammadelta T-cell proliferation or reactivity with mAb M5 indicating the ability of monocytes to stimulate does not involve peripheral membrane components or a glycosyl-phosphatidylinsositol (GPI)-anchored components. Hence it was concluded that the stimulation occurred as a result of intergral membrane proteins including that recognized by mAb M5. The ligand for mAb M5 was on all bovine monocytes and to a lower level on granulocytes but not on lymphocytes. MAb M5 also reacted with sheep monocytes but not with human monocytes or murine macrophages, in agreement with a previous reports that sheep monocytes but not human or mouse mononuclear phagocytes have the capacity to stimulate bovine gammadelta T cells in in vitro cultures. The level of expression of the M5 ligand was not altered by gamma-irradiation or culture of monocytes with lipopolysaccharide but it was decreased following culture with interferon-gamma-containing cell culture supernatants.

Animals↗
PubMed2001

Increased expression of CD23 (Fc(epsilon) receptor II) by peripheral blood monocytes of aids patients.

Monocytes expressing the Fcepsilon receptor II (CD23) play important roles in inflammatory and allergic immune responses. We found that peripheral blood monocytes of AIDS patients express increased levels of CD23, compared with monocytes of healthy HIV-1-seronegative individuals (controls) (p < 0.05). We compared expression of monocyte CD23 with expression of monocyte Fcgamma receptors (CD16, CD32, CD64), plasma/serum levels of IgE (also IgM, IgG, IgA), and Th1 (IFN-gamma) and Th2 (IL-4, IL-10) cytokines. We found that monocyte CD23 expression directly correlated with monocyte CD16 expression (p < 0.01, R = 0.58), which was also increased in AIDS patients; there was no correlation with CD32 or CD64 or with soluble factors in plasma/serum (i.e., IgE, IL-4, IL-10, and IFN-gamma). Interestingly, despite the known ability of IL-10 to downregulate monocyte CD23 expression, plasma IL-10 levels were increased in these AIDS patients compared with controls (p < 0.05). We thus evaluated the effect of AIDS and control plasma or rhIL-10 to regulate CD23 expression by monocytes in cultures (24 hr) of healthy human cells +/- treatment with anti-IL-10R blocking antibody. We found that anti-IL-10R blocking antibody treatment had no effect on monocyte CD23 expression in cultures containing AIDS plasma, but increased monocyte CD23 expression in cultures containing control plasma (p < 0.05) or rhIL-10. In conclusion, the identification of increased monocyte CD23 expression in AIDS patients may further characterize the aberrant activated phenotype of monocytes during the immunopathogenesis of HIV-1 disease. Further, monocyte CD23 expression does not appear to be suppressed by the IL-10-enriched environment in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Products of stimulated monocytes enhance the activity of interferon-gamma.

We have investigated the interaction of interferon-gamma (IFN-gamma) with monocytes or products of stimulated monocytes. We have shown that IFN-gamma does not stimulate IFN-alpha production in monocytes. Staphylococcus aureus (SAC) but not lipopolysaccharide (LPS) induced IFN-alpha secretion by monocytes. However, it was observed that supernatants of monocytes stimulated with IFN-gamma in combination with either LPS or SAC had higher levels of antiviral activity than supernatants of monocytes stimulated only with IFN-gamma. Moreover, the degree of enhancement of antiviral activity was dependent on the dose of either LPS or SAC used to stimulate the monocytes. Supernatants of monocytes stimulated with LPS or SAC enhanced the antiviral activity of IFN-gamma but not IFN-alpha. Thus, LPS- or SAC-stimulated monocytes produced a factor(s) that augmented the biological activity of IFN-gamma. To identify the factor within stimulated monocyte supernatants that was responsible for this enhancement, several monokines were added to IFN-gamma. Tumor necrosis factor (TNF) significantly increased the antiviral activity of IFN-gamma, although TNF by itself had no antiviral activity. Interleukin 1 (IL-1) or granulocyte-monocyte colony-stimulating factor (GM-CSF) did not enhance the activity of IFN-gamma. Our data indicate that the interaction between IFN-gamma and monocytes is bidirectional. Not only can IFN-gamma activate monocytes, but products of stimulated monocytes also enhance the biological activities of IFN-gamma.

Cell Line↗
PubMed1999

High-level porcine endothelial cell expression of alpha(1,2)-fucosyltransferase reduces human monocyte adhesion and activation.

BACKGROUND: Monocyte binding to and activation by human endothelium requires a number of interactions, including those involving sialylated endothelial cell ligands. As porcine endothelial cell transfection with alpha(1,2)-fucosyltransferase has been shown to reduce terminal sialylation, we investigated whether high-level expression of alpha(1,2)-fucosyltransferase by porcine endothelium would reduce human monocyte adhesion and functional activation. METHOD: Purified human monocytes were labeled with 51Cr, and measured for adherence to human or porcine endothelial cell monolayers in the presence of either medium or monoclonal antibodies against monocyte lectins or sialylated endothelial cell ligands. Monocyte production of prostaglandin E2 (PGE2) and interleukin-1beta (IL-1beta) was measured by enzyme-linked immunosorbent assay, using supernatants collected from cultures performed between human monocytes and human or porcine endothelial cell monolayers. Finally, monocyte adhesion and activation were measured after culture with a porcine endothelial cell line transfected with alpha(1,2)-fucosyltransferase, expressing reduced surface expression of terminal Gal alpha(1,3)-Gal and sialic acid residues. RESULTS: Human monocytes adhered by 50% higher levels to porcine endothelium than to human endothelium. This increased level of adherence was associated with augmented monocyte activation, as defined by 3.3-fold higher levels of PGE2 production and 7.3-fold higher levels of IL-1beta production. Monoclonal antibodies against CD62L (L-selectin) on monocytes or CD15s (sialylated Lewis X) on porcine endothelium reduced monocyte adhesion by 38% and 52%, respectively. Porcine endothelial cell transfection with alpha(1,2)-fucosyltransferase reduced terminal sialic acid expression by 65%, monocyte adherence by 50%, and the production of PGE2 and IL-1beta by 67% and 38%, respectively. CONCLUSIONS: Together, these results demonstrate that human monocytes use surface lectins to bind to sialylated carbohydrate structures on porcine endothelium, and indicate that reduction in porcine endothelial cell surface expression of terminally sialylated structures by high-level alpha(1,2)-fucosyltransferase activity reduces monocyte adherence and activation.

Animals↗
PubMed1991

Comparison of the T lymphocyte-dependent induction of angiotensin-converting enzyme and leucine aminopeptidase in cultured human monocytes.

The T lymphocyte-mediated induction of angiotensin-converting enzyme (ACE) in cultured autologous peripheral blood monocytes has been proposed as a model system for the investigation of the in vivo induction of ACE in the monocyte-derived granuloma epithelioid cells of some granulomatous diseases such as sarcoidosis. The studies described here were designed to evaluate the specificity of the model system by comparing the parameters for induction of ACE with those for the induction of another monocyte metallo-ecto-peptidase, leucine aminopeptidase (LAP). The concentration of LAP in freshly isolated monocytes was 0.09 mU/10(6) monocytes (s.e.m. 0.04) and increased to a maximal value of 0.19 mU/10(6) monocytes (s.e.m. 0.32) after 3 days when monocytes were cultured alone. ACE was not detectable in freshly isolated monocytes. However, after 6 days of culture, monocytes contained 0.22 mU ACE/10(6) monocytes (s.e.m. 0.04). Comparison of the levels of ACE and LAP induced during culture of monocytes alone indicated that the induction of these two enzymes were correlated. The induction of both enzymes was further enhanced by the presence of T lymphocytes in a dose-dependent manner. At 4 x 10(6) T lymphocytes per culture, ACE levels increased to 1.81 mU/10(6) monocytes (s.e.m. 0.24) and LAP levels to 1.03 mU/10(6) monocytes (s.e.m. 0.35). The enhancement of ACE activity required autologous lymphocytes, while heterologous T lymphocytes were equally effective in inducing LAP. Comparison of the levels of ACE and LAP induced during coculture of autologous T lymphocytes and monocytes from 21 independent donors, demonstrated no correlation between the induction of ACE and LAP. These data indicate that, although T lymphocytes also enhance the induction of LAP, the underlying mechanism must differ from that of ACE induction.

Cells, Cultured↗
PubMed1992

Monocyte heterogeneity in angiotensin-converting enzyme induction mediated by autologous T lymphocytes.

The ability of monocyte subpopulations to be induced selectively by T lymphocytes to synthesize enhanced levels of angiotensin-converting enzyme (ACE) was examined using an in vitro model employing normal peripheral blood monocytes and T lymphocytes. Separation of monocytes into subpopulations on the basis of buoyant density indicated no difference in the ability of the resulting monocyte subpopulations to produce basal levels of ACE when cultured in the absence of T lymphocytes. However, the subpopulations differed significantly in their ability to synthesize enhanced levels of ACE in response to the presence of autologous T lymphocytes; low-density monocytes were induced by T lymphocytes to synthesize three-fold more ACE than were high-density monocytes. Surface antigen labelling using MoAbs demonstrated that the low-density monocyte subpopulations also had a significantly higher percentage of Leu-M2+ monocytes compared with the high-density monocyte subpopulations. When monocytes were separated on the basis of the presence of the Leu-M2 antigen using an immune rosetting technique, T lymphocytes were able to induce significantly elevated levels of ACE in the Leu-M2+ enriched monocyte subpopulation but were unable to induce ACE beyond basal levels in the Leu-M2(+)-depleted monocyte subpopulation. These results demonstrate that monocytes are heterogeneous with respect to their ability to be induced by T lymphocytes to synthesize ACE. This raises the possibility that selective accumulation of a monocyte subpopulation in the granulomatous inflammation of sarcoidosis may be one of the factors required for elevated ACE synthesis in the resulting granuloma epithelioid cells.

Adult↗
PubMed2007

Human monocytes, but not dendritic cells derived from them, are defective in base excision repair and hypersensitive to methylating agents.

Monocytes and dendritic cells are key players in the immune response. Because dendritic cells drive the tumor host defense, it is important that monocytes and dendritic cells survive cytotoxic tumor therapy. Although most of the anticancer drugs target DNA, the DNA repair capacity of monocytes and dendritic cells has not yet been investigated. We studied the sensitivity of monocytes and monocyte-derived dendritic cells against various genotoxic agents and found monocytes to be more sensitive to overall cell kill and apoptosis upon exposure to methylating agents (e.g., N-methyl-N'-nitro-N-nitrosoguanidine, methyl methanesulfonate, and the anticancer drug temozolomide). On the other hand, upon treatment with the cross-linking chemotherapeutics fotemustine, mafosfamide, and cisplatin, monocytes and dendritic cells responded in the same way. Monocytes were also more sensitive than lymphocytes. The data indicate a defect in the repair of DNA methylation damage in monocytes. Because the expression of the repair protein O(6)-methylguanine-DNA methyltransferase was higher in monocytes than in dendritic cells, and because its inhibition by O(6)-benzylguanine had no effect on the sensitivity of monocytes, we investigated the base excision repair (BER) pathway. In contrast to dendritic cells, monocytes are unable to perform BER following exposure to methylating agents. Expression studies revealed that monocytes lack XRCC1 and ligase IIIalpha, whereas dendritic cells, similar to human lymphocytes, express these repair proteins at a high level. The data revealed a DNA repair defect in a specific human cell population. The BER defect in monocytes may cause them to be selectively killed during tumor therapy with alkylating agents, provoking hematotoxicity and sustained immunosuppression.

Alkylating Agents↗
PubMed1984

Regulation of human peripheral blood monocyte DR antigen expression in vitro by lymphokines and recombinant interferons.

The in vitro regulation of adult human monocyte DR antigen expression was studied. Normally about 75% of freshly obtained human peripheral blood monocytes express DR antigens as determined by anti-DR and complement-mediated cytotoxicity assays. DR expression on monocytes in unfractionated peripheral blood mononuclear cell cultures persisted to variable degrees for up to 5 d of incubation. However, when the mononuclear cells were thoroughly depleted of nonadherent cells, cultured monocytes consistently exhibited progressively decreased DR expression over 2-5 d of incubation. Readdition of nonadherent cells to the adherent cell population prevented or delayed this decrease in monocyte DR antigen expression. Thus, monocyte DR expression diminished markedly during in vitro incubation; however, the presence of nonadherent cells somehow interfered with this process. In other experiments, peripheral adherent monocytes, which had been cultured for 2-3 d to reduce their DR expression, could be induced to reexpress DR antigens after 2 d of incubation with unpurified lymphokine-containing culture supernatants, recombinant human interferon-alpha, or recombinant human gamma interferon (IFN-gamma). The reinduction of DR expression on human monocytes by lymphokines was abrogated by an antiserum produced to the synthetic N-terminal amino acids of human IFN-gamma, indicating that IFN-gamma is the active mediator in the lymphokine-containing preparations. Monocytes cultured with lymphokines or recombinant interferons also could initiate a significantly greater mixed lymphocyte response than control monocytes. Thus, IFN-gamma-containing lymphokines and recombinant interferons are required to induce human monocyte DR expression and accessory cell capacity in vitro, since in their absence monocytes become DR antigen-deficient. Finally, incubation of unfractionated human mononuclear cells with anti-human IFN-gamma also promoted the loss of monocyte DR expression. These findings suggest that resting lymphocytes are probably capable of producing sufficient IFN-gamma in vitro to result in the maintenance of the monocyte DR phenotype.

Cells, Cultured↗
PubMed1999

Alterations of monocyte function in patients with growth hormone (GH) deficiency: effect of substitutive GH therapy.

GH deficiency (GHD) is associated with increased prevalence of atherosclerosis and cardiovascular morbidity. Because monocytes play a crucial role in the development of atherosclerosis, we investigated in the present study the effect of GH deficiency and subsequent GH replacement on monocytic function in hypopituitary subjects. Twelve patients were randomized to receive GH replacement therapy (either 3 or 6 microg/kg x day, s.c.) for 3 months. Plasma levels and monocyte production of cytokines and monocyte adhesion to endothelium were determined in controls and patients with GHD before and after GH treatment. Before GH therapy, patients with GHD had increased basal plasma tumor necrosis factor-alpha (TNF alpha; 220% over control values; P = 0.004) and interleukin-6 (IL-6; 340% over control values; P 0.0009) levels. Basal monocyte production of both cytokines was also significantly higher in patients with GHD [484% over control values for TNF alpha (P = 0.0007); 1479% over control values for IL-6 (P = 0.035)]. GH treatment for 3 months led to a reduction in plasma TNF alpha (135% over control values; P = 0.03, pre- vs. post-GH therapy), monocyte TNF alpha production (204% over control values; P = 0.01), plasma IL-6 (219% over control values; P = 0.07), and monocyte IL-6 production (448% over control values; P = 0.01). Plasma TNF alpha levels positively correlated with monocyte TNF alpha production in patients with GHD both before and after GH therapy (P = 0.003 and P = 0.049, respectively). A positive correlation (P = 0.0003) was also observed between monocyte TNF alpha production and monocyte IL-6 production. There were no correlations between these plasma cytokine levels or monocyte cytokine production and parameters of body composition, lipid profile, or IGF-I and IGF-binding protein-3 levels. Before GH treatment, adhesiveness of monocytes to cultured aortic endothelial cells was also enhanced. This alteration was not reversed by GH administration. In conclusion, our results demonstrate that markers of monocyte activation are increased in patients with GHD and that GH replacement partly reduces these abnormalities. Reduction of cellular activation of monocytes by GH therapy could potentially contribute to reduce the risk of cardiovascular events in patients with GHD.

Adult↗
PubMed2005

Blood platelet and monocyte activations and relation to stages of liver cirrhosis.

AIM: Blood platelets (plt) and monocytes are the cells that play a crucial role in the pathogenesis of liver damage and liver cirrhosis (LC). In this paper, the analysis of mutual relationship between platelets and monocytes activation in LC was conducted. METHODS: Immunofluorescent flow cytometry was used to measure the percentage of activated platelet populations (CD62P, CD63), the percentage of plt-monocyte aggregates (pma) (CD41/CD45), and activated monocytes (CD11b, CD14, CD16) in the blood of 20 volunteers and 40 patients with LC. Platelet activation markers: sP-selectin, platelet factor 4 (PF4), beta-thromboglobulin (betaTG) and monocyte chemotactic peptide-1 (MCP-1) were measured and compared in different stages of LC. RESULTS: Platelet activation with the increase in both betaTG serum concentration and elevation of plt population (CD62P and CD63 as well as MIF CD62P and CD63) is elevated as LC develops and thrombocytopenia rises. There is a positive correlation between medial intensity of fluorescence (MIF) CD62P and MIF CD63 in LC. We did not show any relationship between monocyte activation and pma level. SP-selectin concentration correlates positively with plt count and pma, and negatively with stage of plt activation and MIF CD62P and MIF CD63. There was no correlation between MCP-1 concentration and plt, monocyte activation as well as pma level in LC. CD16 monocytes and MIF CD16 populations are significantly higher in the end stage of LC. A positive correlation occurs between the value of CD11b monocyte population and MIF CD14 and MIF CD16 on monocytes in LC. CONCLUSION: Platelet and monocyte activation plays an important role in LC. Platelet activation stage does not influence monocyte activation and production of plt aggregates with monocytes in LC. With LC development, thrombocytopenia may be the result of plt consumption in platelet-monocyte aggregates.

Adult↗
PubMed2001

Activated T lymphocytes regulate hyaluronan binding to monocyte CD44 via production of IL-2 and IFN-gamma.

Interactions of the cell surface proteoglycan CD44 with the extracellular matrix glycosaminoglycan hyaluronan (HA) are important during inflammatory immune responses. Our previous studies indicated that monocyte HA binding could be induced by TNF-alpha. Moreover, monocyte HA binding could be markedly up-regulated by culturing PBMC with anti-CD3 (TCR complex) mAbs. The present study was undertaken to identify soluble factors and/or cell surface molecules of activated T lymphocytes that might regulate HA binding to monocytes. Abs to IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-10, IL-15, GM-CSF, IFN-gamma, and TNF-alpha were tested for their effects on anti-CD3 mAb-, Con A-, and PMA/ionomycin-mediated monocyte HA binding in PBMC cultures. Anti-TNF-alpha, anti-IL-2, and anti-IFN-gamma Abs, when added together to PBMC cultures, completely blocked Con A- and partially blocked anti-CD3- and PMA/ionomycin-induced monocyte HA binding. Furthermore, when added together to PBMC cultures, IL-2 and TNF-alpha induced high levels of monocyte HA binding. Likewise, IFN-gamma augmented TNF-alpha-induced monocyte HA binding. To investigate the role of T cell-monocyte direct contact in induction of monocyte HA binding, we studied PMA/ionomycin-activated, paraformaldehyde-fixed CD4(+) T cells in these assays. Fixed, PMA/ionomycin-activated CD4(+) T lymphocytes induced monocyte HA binding, but direct T cell-monocyte contact was not required. Moreover, anti-IFN-gamma and anti-TNF-alpha Abs blocked fixed PMA/ionomycin-activated CD4(+) T cell-induced monocyte HA binding. Taken together, these studies indicate roles for soluble T lymphocyte-derived factor(s), such as IL-2 and IFN-gamma, and a role for monocyte-derived TNF-alpha in Con A-, TCR complex-, and PMA/ionomycin-induced HA binding to monocyte CD44.

Binding Sites↗
PubMed2002

Monocyte apoptosis in dialysis patients is Fas ligand-mediated.

BACKGROUND: The mononuclear phagocyte system plays an important role in host defense. Since dialysis patients have been reported to show enhanced leukocytes apoptosis, we evaluated the mechanism of increased apoptosis of monocytes in dialysis patients. METHODS: Apoptotic studies were carried out on monocytes isolated from dialysis patients as well as healthy subjects. The effect of dialysis sera and membranes was evaluated on monocyte apoptosis as well as monocyte expression of proapoptotic proteins such as Fas and FasL. To confirm the role of FasL, we evaluated the effect of activated secretory products on T cell apoptosis. In addition, we studied FasL content of dialysis sera and supernatants of activated monocytes. RESULTS: Monocytes isolated from dialysis patients (MDP) showed a greater magnitude of apoptosis when compared to monocytes isolated from healthy subjects (MHS) (MHS, 3.6 +/- 1.1% vs. MDP, 24.3 +/-1.4%). Sera of hemodialysis patients (SHD) promoted (p < 0.001) apoptosis of MHS when compared to pooled control sera (HPS) (HPS, 0.8 +/- 0.5% vs. SHD, 11.5 +/- 0.5% apoptotic cells/field). Dialysis membranes, cellulose acetate membranes in particular, promoted monocyte apoptosis. Interestingly, anti-FasL antibodies partly inhibited dialysis sera-induced monocyte apoptosis. Dialysis membranes also modulated monocyte expression of both Fas and FasL. Secretory products of activated monocytes also promoted T cell apoptosis. Dialysis sera and activated monocyte secretory products showed increased FasL content. CONCLUSIONS: These results suggest that dialysis patients have an increased rate of monocyte apoptosis, which is mediated through a uremic milieu (serum factors). One of these serum factors seems to be FasL. In addition, dialysis membranes seem to promote apoptosis independent of the uremic milieu. The present study provides a mechanistical insight into the enhanced apoptosis of monocytes in dialysis patients.

Apoptosis↗
PubMed1990

Cytotoxicity of activated monocytes on endothelial cells.

Unstimulated human monocytes did not express appreciable levels of cytotoxicity on normal human umbilical vein endothelial cells (EC) in a 24-48 hr TdR release assay. On activation with IFN-gamma and LPS, monocytes had appreciable cytotoxicity on EC. Monocyte cytotoxicity on EC was not dependent on the presence of contaminating lymphoid cells. Recombinant TNF, IL-1, and IL-6 as well as monocyte supernatants did not exert a cytotoxic effect on EC. Moreover, anti-TNF, anti-IL-1, and anti-IL-6 antibodies, as well as scavengers of reactive oxygen intermediates, did not affect the cytotoxicity of activated monocytes on EC. Antibodies against the beta-chain (CD18) of leukocyte integrins inhibited the adhesion and cytotoxicity of activated monocytes on EC. Pretreatment of EC with IL-1 augmented the adhesion of monocytes on EC. Normal monocytes were not cytotoxic on IL-1-pretreated EC and IL-1 treatment did not increase the susceptibility of EC to activated monocytes. Thus adhesion is necessary but not sufficient for monocyte killing of EC. Anti-alpha L (LFA-1) antibodies markedly reduced monocyte cytotoxicity on EC, although anti-alpha X (p150) antibodies had only a modest effect. Anti-alpha M (Mac-1/CR3) antibodies were intermediate inhibitors of EC killing by activated monocytes. Thus, alpha L, beta 2 (LFA-1), and, to a lesser extent, alpha M, beta 2 (Mac-1/CR3) and alpha X, beta 2 (p 150, 95) integrins are the main adhesive structures involved in the cytotoxic interaction of activated monocytes with EC. Monocyte-mediated damage of EC could play a role as a mechanism of tissue injury under conditions of local or systemic activation of mononuclear phagocytes.

Antigens, Differentiation↗