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PubMed1994

Lipolysaccharide-induced monocyte retention in the lung. Role of monocyte stiffness, actin assembly, and CD18-dependent adherence.

Blood monocytes and monocyte-derived macrophages accumulate in the lungs and can modulate pulmonary inflammatory and reparative processes through their elaboration of cytokines and growth factors. Endotoxemia, often a prelude to acute lung injury, induces a monocytopenia, likely resulting from monocyte accumulation in the lung. We hypothesized that LPS would induce monocyte lung retention by increasing monocyte stiffness and thereby diminishing the cell's ability to deform and transit the narrow pulmonary capillary network, and that LPS would induce CD18-dependent adhesion of monocytes to endothelium, prolonging their retention. LPS induced a rapid and concentration-dependent increase in human monocyte stiffness, net filamentous actin assembly, and retention in a filtration model of pulmonary capillaries. These LPS-induced responses were dependent on the integrity of actin filaments in that cytochalasin D, an agent that disrupts filamentous actin assembly, attenuated each of these processes. LPS induced CD18-dependent and -independent human monocyte adhesion to unstimulated human endothelial cell monolayers. In vivo, rabbit monocytes were retained in the lungs of animals rendered endotoxemic. Pretreatment of monocytes ex vivo with LPS enhanced their lung retention suggesting that LPS was acting directly on monocytes. Initial lung retention during endotoxemia was attenuated by inhibiting monocyte F-actin assembly with cytochalasin D. Anti-CD18 Abs caused a slight decrease in initial retention of monocytes, but led to a 90% inhibition of retention by 2 h. Control IgG had no effect. These data suggest that the initial retention of monocytes in the lung during endotoxemia is dependent on alterations in their stiffness and assembly/organization of F-actin, and that CD18-dependent adhesive mechanisms prolong monocyte retention in the lung during this process.

Actins↗
PubMed1992

Interactions between HIV-infected monocytes and the extracellular matrix: increased capacity of HIV-infected monocytes to adhere to and spread on extracellular matrix associated with changes in extent of virus replication and cytopathic effects in infected cells.

Monocytes express cell surface receptors for extracellular matrix (ECM) proteins of basement membranes. These receptors are engaged during extravasation of cells through capillary endothelium into tissue. The number of human immunodeficiency virus (HIV)-infected monocytes that adhered to ECM over 2 h was threefold higher than that of uninfected control cells. This difference was ECM specific and was not observed with a bovine serum albumin substrate. Enhanced adhesion to ECM was evident in monocytes by 4 days after HIV infection and increased through 10 days. Monocytes exposed to a T cell-tropic HIV strain that binds to but does not replicate in monocytes showed no changes in adherence to ECM. Thus, productive infection of monocytes by HIV induces a significant increase in the capacity of these cells to interact with ECM. Enhanced adhesion of HIV-infected monocytes to ECM was associated with increased spreading: at 12 h, sixfold more HIV-infected monocytes were spread on ECM than were uninfected control cells. Cell processes of HIV-infected monocytes formed a complex network on ECM: many of these cells expressed HIV proteins as detected by indirect immunofluorescence. HIV-associated cytopathic effects and levels of virion-associated reverse transcriptase activity depended on the substrate to which monocytes were attached. Virus replication and cytopathic effects in monocytes adhered to ECM, fibronectin, or plastic alone were comparable. In contrast, HIV-infected monocytes attached to laminin showed a significant increase in virus replication and in extent of cytopathic effects through 2 weeks after infection. The lowest levels of HIV replication and cytopathic effects were in monocytes attached to collagen IV. Interactions between monocytes and ECM profoundly affect the manner in which these cells control HIV infection: HIV infection changes the capacity of infected monocytes to attach and spread on ECM; attachment to ECM alters the extent of virus replication in infected cells.

Cell Adhesion↗
PubMed1981

Human monocyte spreading induced by factor Bb of the alternative pathway of complement activation. A possible role for C5 in monocyte spreading.

The central serine esterase of the alternative pathway of complement (APC) activation, activated factor B (Bb), has been shown recently to induce murine macrophages and human monocytes to become spread on a glass substrata. It has also been established that to induce the spreading reaction, the catalytic site of the Bb enzyme must be structurally intact since treatment of Bb with heat (56 degrees C for 30 min) or diisopropylfluorophosphate (10(-3) M) destroyed both enzymatic and spreading activities. In the C3b,Bb complex, Bb exhibits restricted substrate specificity for C3 and C5. With this in mind, the role of C3 and C5 in the monocyte spreading reaction was explored in the present study. Expression of C3 and C5 on the surface of human peripheral blood monocytes was investigated by the direct fluorescent antibody technique employing fluorescein isothiocyanate-conjugated anti-C3 or C5 F(ab')2 antibody fragments. It was found that C3 and C5 were present on 6 +/- 7% of freshly prepared monocytes and that expression of C5, but not C3, increased to 70 +/- 6% when monocytes were incubated for 3 d in serum-free medium. Biosynthesis of C5 was indicated when it was found that under serum-free conditions, monocytes incorporated [3H]leucine into immunoprecipitable C5 with an apparent mol wt of 180,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The role of C3 and C5 in the monocyte spreading reaction induced by factor Bb was explored by testing for the ability of anti-C3 and anti-C5 Fab' antibody fragments to block monocyte spreading. It was found that anti-C5 Fab' inhibited by up to 100% the 3-h human monocyte spreading reaction induced by Bb; in contrast, anti-C3 Fab' or anti-C4 Fab' inhibited by less than 10%. That the inhibitory effect of anti-C5 Fab' was exerted directly on the monocyte was established when it was found that the 3-h monocyte spreading reaction was significantly inhibited by pretreating monocytes with anti-C5 Fab' for 20 min and then washing before the addition of Bb. The specificity of the inhibitory effect of anti-C5 Fab' was established by quantitatively absorbing the antibody fragments with polyacrylamide gel-purified C5 antigen: greater than 4 microgram of C5 absorbed by 100% the inhibitory activity of 10-20 microgram of anti-C5 Fab'. That factor Bb exerted its effect on monocytes by interacting directly with cell surface C5 was indicated when it was found that purified C5 inhibited the monocyte spreading reaction induced by Bb; greater than 25 microgram of C5 inhibited by 100% the spreading reaction induced by 3 microgram factor Bb.

Cell Adhesion↗
PubMed1984

HLA-DR human histocompatibility leukocyte antigens-restricted lymphocyte-monocyte interactions in the release from monocytes of acidic isoferritins that suppress hematopoietic progenitor cells.

Acidic isoferritins, which under normal conditions are released from monocytes and macrophages, have a suppressive effect in vitro on granulocyte-macrophage, erythroid, and multipotential hematopoietic progenitor cells. Cell interactions modulating the release of acidic isoferritin-inhibitory activity (AIFIA) from human monocytes were investigated using the bone marrow granulocyte-macrophage progenitor cells as a target cell assay for assessing AIFIA. Monocytes, in the absence of T lymphocytes, released AIFIA when allowed to condition culture medium at 10(4) or higher concentrations of monocytes/ml. However, subpopulations of T lymphocytes modulated the release of AIFIA from monocytes. OKT8+- and OKT4+-T lymphocytes were obtained from E-rosette-positive lymphocytes by using T lymphocyte subset-specific monoclonal antibodies in either a complement-dependent cytotoxicity test to select negatively for the cells or by selection using a "panning" procedure. OKT8+-T lymphocytes suppressed completely and OKT4+-T lymphocytes enhanced the constitutive release of AIFIA from monocytes. OKT4+ lymphocytes also induced the release of AIFIA from concentrations of 10(3) monocytes/ml which did not release measurable amounts of AIFIA by themselves. The release of AIFIA from monocytes involved HLA-DR+-monocytes and -T lymphocytes. Pulsing monocytes with monoclonal antibodies to framework determinants on HLA-DR molecules, in the absence of complement, did not influence the constitutive release of AIFIA. Pulsing monocytes or T lymphocyte subpopulations with such antibodies, in the absence of complement, blocked the suppressing and inducing activities of the appropriate subpopulations of T lymphocytes. Monoclonal antibodies to common determinants shared by HLA-A, B, and C molecules did not block these cellular interactions. Treating monocytes and T lymphocytes in a complement-dependent cytotoxicity test with dilutions of the anti-HLA-DR antibodies that did not block the cellular interactions removed the populations of monocytes constitutively releasing AIFIA and the T lymphocyte subsets modulating this release. Modulation of the release of AIFIA from monocytes by T lymphocyte subpopulations required the use of autologous cells, cells from HLA-identical siblings, or unrelated donors matched for HLA-DR. Matching for only one HLA haplotype gave partial responses and this was seen in testing cells from related individuals as well as among unrelated test combinations. These cellular interactions were not detected with HLA-DR-incompatible cells differing for two HLA-DR antigens. Admixture of such HLA-DR- incompatible allogeneic cells did not interfere with the regulation of AIFIA release in the autologous cell interactions. Thus, release of AIFIA from monocytes is restricted genetically by HLA-DR at the level of T lymphocyte-monocyte interactions. The genetic determinants on the HLA-class II molecules that induce stimulation in vitro in mixed lymphocyte culture (i.e., HLA-D), however, were not involved in this effort.

Antilymphocyte Serum↗
PubMed1987

Human monocyte-mediated cytotoxicity: the use of Ig-bearing hybridomas as target cells to detect trigger molecules on the monocyte cell surface.

We recently reported the preparation and characterization of a monoclonal antibody, 32.2, specific for the high-affinity Fc receptor (FcR) for IgG on human monocytes. We have utilized the hybridoma cell line producing this antibody as a target for monocyte-mediated cytotoxicity. The hybridoma was selected for stable sublines that expressed high quantities of surface 32.2 immunoglobulin (Ig) through flow cytometry. Monocyte-mediated cytotoxicity, with these sublines used as targets, was evaluated with the use of a 51Cr-release assay. It was found that monocytes could efficiently lyse the hybridoma cells (HC 32.2) bearing surface Ig directed to the high-affinity FcR. Consistent with the specificity of the 32.2 antibody for an epitope on the high-affinity receptor outside of the ligand binding site, human IgG did not block monocyte killing of HC 32.2. In contrast, monocytes could not mediate lysis of hybridoma cells bearing high levels of antibody directed to other monocyte cell surface molecules, in particular, class I MHC molecules, the C3bi receptor, and the My 23 antigen. The effect of IFN-gamma on the ability of monocytes to mediate lysis of the 32.2 Ig-bearing hybridomas was also assessed. Monocytes cultured in the absence of IFN-gamma could lyse the hybridoma line expressing high levels of 32.2 Ig as efficiently as monocytes cultured in the presence of IFN-gamma. However, untreated monocytes were less able than IFN-gamma-treated monocytes to kill HC 32.2 expressing lower levels of Ig. Thus, IFN-gamma may enhance the efficiency of monocyte-mediated antibody-dependent killing under conditions where limited antibody is available on the target. These studies demonstrate that the high-affinity FcR on monocytes can act as a cytotoxic trigger molecule for killing of tumor cell targets and that this trigger does not require specific binding to the Fc binding epitope. These results further encourage possible clinical application of the 32.2 monoclonal antibody in tumor therapy.

Animals↗
PubMed1986

Improved methods for purification and depletion of monocytes from bovine peripheral blood mononuclear cells. Functional evaluation of monocytes in responses to lectins.

We have compared different techniques for the enrichment and depletion of monocytes from bovine peripheral blood mononuclear cells. Adherence to plasma-coated gelatin was the most efficient and reproducible method for enrichment of monocytes (80% monocytes), whereas depletion of peripheral blood mononuclear cells of monocytes (0.3% monocytes and less) was best achieved by defibrination of the blood from which the PBM were separated. In both instances, purity of the cell population could be improved further by an additional step, namely, FACS sorting with a monocyte-specific monoclonal antibody to purify monocytes (97% monocytes and more), and adherence to polystyrene to remove residual monocytes from defibrinated PBM (0.1% monocytes and less). Depletion of monocytes abolished the response of PBM to concanavalin A and phytohaemagglutinin. The lectin-induced response could be restored by adding gelatin/plasma purified monocytes. This activity of monocytes could be replaced by 2-mercaptoethanol.

Animals↗
PubMed1997

Reduction of monocyte-platelet interaction and monocyte activation in patients receiving antiplatelet therapy after coronary stent implantation.

BACKGROUND: Monocyte activation induces different procoagulant and proadhesive inflammatory responses and thus may play a role in thrombotic complications after coronary interventions. Monocyte-platelet interaction may trigger these effects inducing monocyte activation. AIMS: To characterize the effect of antiplatelet vs anticoagulation therapy on monocyte-platelet interaction and monocyte function after intracoronary stenting. METHODS AND RESULTS: Immediately before, and during the first 12 days after successful coronary stenting, monocyte-platelet conjugates and monocyte function were assessed by flow cytometric detection of GPIIb/IIIa (CD41) on monocytes and by monocyte surface exposure of Mac-1 (CD11b/CD18) and L-selectin (CD62L). Twenty patients receiving combined antiplatelet therapy (ticlopidine, aspirin) were compared to 20 patients with standard anticoagulation (phenprocoumon, overlapping heparin, aspirin). Before stenting, monocyte-platelet conjugates and Mac-1 surface expression in both groups were significantly increased, while L-selectin was significantly diminished. Anticoagulation did not change these variables significantly during the subsequent 12 days. In contrast, antiplatelet therapy reduced platelet-monocyte conjugates by 46 +/- 9.3% (mean +/- SEM, P = 0.0019) within 4 days, which was associated with a decrease in Mac-1 expression (28 +/- 6.7%, P = 0.0013) and an increase in L-selectin (56 +/- 15.0%, P = 0.0061). CONCLUSION: After intracoronary stenting, combined antiplatelet therapy, but not anticoagulation, causes reduction of monocyte-platelet interaction, which is associated with monocyte deactivation. This may contribute to a decreased risk for thrombotic events.

Adult↗
PubMed1991

Lactoferrin inhibits or promotes Legionella pneumophila intracellular multiplication in nonactivated and interferon gamma-activated human monocytes depending upon its degree of iron saturation. Iron-lactoferrin and nonphysiologic iron chelates reverse monocyte activation against Legionella pneumophila.

We have been exploring the role of iron in the pathogenesis of the intracellular bacterial pathogen Legionella pneumophila. In previous studies, we have demonstrated that L. pneumophila intracellular multiplication in human monocytes is iron dependent and that IFN gamma-activated monocytes inhibit L. pneumophila intracellular multiplication by limiting the availability of iron. In this study, we have investigated the effect on L. pneumophila intracellular multiplication of lactoferrin, an iron-binding protein which is internalized via specific receptors on monocytes, and of nonphysiologic iron chelates which enter monocytes by a receptor-independent route. Apolactoferrin completely inhibited L. pneumophila multiplication in nonactivated monocytes, and enhanced the capacity of IFN gamma-activated monocytes to inhibit L. pneumophila intracellular multiplication. In contrast, iron-saturated lactoferrin had no effect on the already rapid rate of L. pneumophila multiplication in nonactivated monocytes. Moreover, it reversed the capacity of activated monocytes to inhibit L. pneumophila intracellular multiplication, demonstrating that L. pneumophila can utilize iron from the lactoferrin-lactoferrin receptor pathway. The capacity of iron-lactoferrin to reverse monocyte activation was dependent upon its percent iron saturation and not just its total iron content. Similarly, the nonphysiologic iron chelates ferric nitrilotriacetate and ferric ammonium citrate completely reverse and ferric pyrophosphate partially reversed the capacity of IFN gamma-activated monocytes to inhibit L. pneumophila intracellular multiplication, demonstrating that L. pneumophila can utilize iron derived from nonphysiologic iron chelates internalized by monocytes independently of the transferrin and lactoferrin endocytic pathways. This study suggests that at sites of inflammation, lactoferrin may inhibit or promote L. pneumophila intracellular multiplication in mononuclear phagocytes depending upon its degree of iron saturation. In addition, this study suggests a potential role for PMN in host defense against L. pneumophila--providing apolactoferrin to infected monocytes--and it supports the concept that PMN and monocytes may cooperate in host defense against intracellular parasites and other pathogens.

Apoproteins↗
PubMed1984

Methods in laboratory investigation. Isolation of guinea pig monocytes and Kurloff cells: characterization of monocyte subsets by morphology, cytochemistry, and adherence.

Guinea pig mononuclear cells were separated from peripheral blood using high-density Ficoll-Hypaque, following which the monocytes and Kurloff cells were isolated using counterflow centrifugation elutriation and Percoll gradient centrifugation. Monocytes were obtained in four counterflow centrifugation elutriation fractions. Small monocytes (283 micron3) constituted 33% of all monocytes and were acid phosphatase negative, nonadherent cells with a scant cytoplasm but characteristic reniform nucleus. Although present in low purity after counterflow centrifugation elutriation, they were enriched using Percoll gradients to 35%. Large monocytes (317 micron3) comprised 41% of all monocytes and were obtained in 81% purity by counterflow centrifugation elutriation. They were adherent cells positive for acid phosphatase and nonspecific esterase. Peroxidase-positive cells constituted 41 and 33% of the small and large monocytes, respectively. Intermediate-sized monocytes (300 micron3) comprised a mixture of monocytes with characteristics of both small and large monocytes. Very large monocytes (354 micron3) were peroxidase-negative, strongly adherent cells with a distinctive morphology characterized by a spherical nucleus and highly vacuolated cytoplasm. They comprised 7% of the total monocytes and are a heretofore unrecognized cell type in the circulation. These procedures also isolated Kurloff cells in high purity and yield. Kurloff cells are distinct to the guinea pig and were nonadherent cells that did not stain for acid phosphatase, peroxidase, or nonspecific esterase. This is the first report of the successful isolation of Kurloff cells as well as monocytes other than human into fractions that differ in size and function.

Acid Phosphatase↗
PubMed1983

Cytochemical, functional, and proliferative characteristics of promonocytes and monocytes from patients with monocytic leukemia.

This article deals with a prospective study on the cytochemical, functional, and proliferative characteristics of promonocytes and bone marrow and peripheral blood monocytes of 20 patients with acute monocytic leukemia and 7 patients with chronic monocytic leukemia. The results show a wide variation in the peroxidase and esterase activities in these cells, whereas the percentages of mononuclear phagocytes with Fc gamma and C3b receptors did not differ appreciably from those in normal individuals. A discriminant analysis of these data and corresponding data from normal individuals showed that a below-normal peroxidase activity of circulating monocytes has predictive value for the presence of monocytic leukemia; a below-normal esterase activity has less, but nevertheless some, predictive value in this respect. An increase in the percentage of circulating monocytes, a decrease in the percentage of Fc gamma or C3b receptors, and a decline in the ability to phagocytose bacteria has no predictive value for the presence of monocytic leukemia. The mean percentage of patients' promonocytes that incorporated 3H-thymidine amounted to 80.9%, which is close to the control value in normal individuals. The mean values for the labeling indices of cultured bone marrow and peripheral blood monocytes are 1.0% and 0.74%, respectively; when 3H-thymidine was added to whole blood, the labeling index of the monocytes amounted to 3.6%. These percentages are only a little higher than those found for monocytes of normal individuals. These results indicate that the majority of the circulating monocytes in acute and chronic monocytic leukemia are not actively dividing or blast cells.

Bone Marrow Cells↗
PubMed1996

Blood monocyte activation in rheumatoid arthritis: increased monocyte adhesiveness, integrin expression, and cytokine release.

Infiltration of the synovium by mononuclear cells, namely lymphocytes and monocytes, is one of the main features of rheumatoid arthritis (RA) and is considered to be responsible for the development of the disease. In this study in 31 consecutive patients with RA, we investigated whether peripheral blood monocytes exhibited markers of cellular activation related to cell migration. Using flow cytometry with the respective specific antibodies, we studied the expression of integrins CD11a, CD11b, CD11c, CD49d (VLA-4), and CD49e (VLA-5) on monocytes from patients with RA and from normal (N) subjects. IL-1 beta, IL-6, and tumour necrosis factor-alpha (TNF-alpha) production by cultured monocytes was measured by immunoassay. Adhesiveness of monocytes was studied on various surfaces (plastic, human fibronectin, gelatin-coated plasma, subendothelial matrix) and on cultured endothelial cells under basal conditions or after stimulation by IL-1 beta. An increased number of CD14+ monocytes (Mo) from RA patients expressed the CD11b molecule (RA Mo = 90.3%, N Mo = 83.4%, P < 0.005). The expression of CD11b on CD14+ monocytes was significantly increased in RA patients (median fluorescence intensity (FI): RA Mo = 145 (range 80-466) units; normal Mo = 95 (range 24-164) units; P < 0.003). Production of extracellular IL-1 beta and IL-6 by RA monocytes was significantly enhanced compared with monocytes from normal subjects (IL-1 beta: RA = 2.65 +/- 0.91 ng/ml versus N = 1.35 +/- 0.85 pg/ml, P < 0.05; IL-6: RA = 4.83 +/- 0.90 ng/ml versus N = 2.40 +/- 0.95 ng/ml, P < 0.05). Compared with normal monocytes, RA monocytes exhibited increased adhesion to the various surfaces studied (plastic, P < 0.01; fibronectin, P < 0.01; and gelatin-coated normal or RA plasma, P < 0.01) as well as to unstimulated (P < 0.01) and IL-1 beta-stimulated endothelial cells (IL-1 beta for 4 h, P < 0.05; IL-1 beta for 24h, P < 0.05). In our study, blood monocytes from RA patients exhibited features of activation related to cell adhesion.

Arthritis, Rheumatoid↗
PubMed2002

Injury induces increased monocyte expression of tissue factor: factors associated with head injury attenuate the injury-related monocyte expression of tissue factor.

BACKGROUND: Activated monocytes are able to express tissue factor (TF), a potent procoagulant. The effect of injury on monocyte TF expression is not known. We have found that patients with head injury (HI) have increased antithrombin activity and decreased platelet function compared with non-head-injured trauma patients. Our objective was to determine whether injury increases TF expression by monocytes and whether this increased TF expression is attenuated in patients with HI. METHODS: We prospectively enrolled 37 trauma patients (meeting the entry criterion of an Injury Severity Score [ISS] > or = 9) and 11 healthy control subjects. We sampled blood on arrival and then at 24, 48, and 72 hours. We performed flow cytometry with antibody markers for monocytes (CD14), platelets (CD42a), and TF. We compared results of patients with HI (Glasgow Coma Scale score < or = 9 and Abbreviated Injury Scale Head/Neck score > or = 3) with patients without HI and with controls. RESULTS: Patients had a mean ISS of 23.9 +/- 2.3 (+/- SEM), mean age of 45 +/- 3 years, and mean length of stay of 17.9 +/- 3.2 days. Seventy-six percent were men, and 97% had blunt trauma. The overall mortality rate was 11%. Trauma patients had greater monocyte TF expression than controls for all time periods (p < 0.05). Trauma patients with HI had elevated monocyte TF expression compared with controls for the initial and 24-hour time periods, but they subsequently had more rapid return of monocyte TF expression to baseline (despite a higher ISS) than trauma patients without HI. Trauma patients both with and without HI had increased platelet-monocyte binding at each time versus controls. CONCLUSION: Trauma induces TF expression on monocytes. Patients with HI have attenuation of this expression by 24 hours after injury. The attenuation of TF expression by monocytes in HI parallels the increase in AT and the decrease in platelet function seen after HI. The correlation of TF expression with platelet-monocyte binding suggests that platelet binding may lead to monocyte activation.

Adult↗
PubMed1998

Helicobacter pylori lipopolysaccharide binds to CD14 and stimulates release of interleukin-8, epithelial neutrophil-activating peptide 78, and monocyte chemotactic protein 1 by human monocytes.

Helicobacter pylori gastritis is characterized by leukocyte infiltration of the gastric mucosa. The aims of this study were to determine whether H. pylori-derived factors stimulate chemokine release from human monocytes and to ascertain whether H. pylori lipopolysaccharide (LPS) may be responsible for this effect. Human peripheral blood monocytes were exposed to an H. pylori water extract (HPE) or to purified H. pylori LPS. Levels of the chemokines interleukin-8 (IL-8), epithelial neutrophil-activating peptide 78 (ENA-78), and monocyte chemotactic protein 1 (MCP-1) were measured by enzyme-linked immunosorbent assay. The contribution of H. pylori LPS to monocyte activation was determined by using the LPS antagonist Rhodobacter sphaeroides lipid A (RSLA) and a blocking monoclonal antibody to CD14 (60bca). HPE increased monocyte secretion of IL-8, ENA-78, and MCP-1. Heat treatment of HPE did not reduce its ability to activate monocytes. Purified H. pylori LPS also stimulated monocyte chemokine production but was 1,000-fold less potent than Salmonella minnesota lipid A. RSLA blocked H. pylori LPS-induced monocyte IL-8 release in a dose-dependent fashion (maximal inhibition 82%, P < 0.001). RSLA also inhibited HPE-induced IL-8 release (by 93%, P < 0.001). The anti-CD14 monoclonal antibody 60bca substantially inhibited IL-8 release from HPE-stimulated monocytes (by 88%, P < 0.01), whereas the nonblocking anti-CD14 monoclonal antibody did not. These experiments with potent and specific LPS inhibitors indicate that the main monocyte-stimulating factor in HPE is LPS. H. pylori LPS, acting through CD14, stimulates human monocytes to release the neutrophil-activating chemokines IL-8 and ENA-78 and the monocyte-activating chemokine MCP-1. Despite its low relative potency, H. pylori LPS may play an important role in the pathogenesis of H. pylori gastritis.

Chemokine CCL2↗
PubMed2003

Platelet-monocyte complexes support monocyte adhesion to endothelium by enhancing secondary tethering and cluster formation.

OBJECTIVE: Adhesion of monocytes to endothelium can be supported by monocyte-monocyte interactions resulting in the formation of cell aggregates at the vessel wall (clusters). Since platelets that are bound to the injured vessel wall support monocyte adhesion and platelet activation in the circulation leads to formation of platelet-monocyte complexes (PMCs), we examined whether adhesion of PMCs to the vessel wall enhances monocyte clustering. METHODS AND RESULTS: The effect of PMC formation in monocyte adhesion and clustering on human umbilical vein endothelial cells (HUVECs) was studied in vitro with a perfusion system. In the presence of 10% to 20% PMCs, monocyte adhesion and cluster formation to stimulated HUVECs increased 2-fold above levels obtained with pure monocytes. While the observed effects increased with higher PMC levels, blocking-monoclonal antibodies directed against platelet-associated P-selectin or monocyte P-selectin glycoprotein ligand-1 (PSGL-1) reversed adhesion and clustering to control values. In the presence of PMCs, blocking L-selectin decreased adhesion by 25%. When PMCs were present, clustering was only supported by L-selectin at higher shear. These data indicate that monocyte adhesion to the vessel wall is enhanced by PMC-mediated monocyte secondary tethering. These interactions are mainly mediated by P-selectin and PSGL-1. CONCLUSIONS: PMCs in the circulation might be proatherogenic, and prevention of their formation is a possible therapeutic goal.

Antibodies, Monoclonal↗
PubMed1991

Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein.

Incubation of cocultures of human aortic endothelial (HAEC) and smooth muscle cells (HASMC) with LDL in the presence of 5-10% human serum resulted in a 7.2-fold induction of mRNA for monocyte chemotactic protein 1 (MCP-1), a 2.5-fold increase in the levels of MCP-1 protein in the coculture supernatants, and a 7.1-fold increase in the transmigration of monocytes into the subendothelial space of the cocultures. Monocyte migration was inhibited by 91% by antibody to MCP-1. Media collected from the cocultures that had been incubated with LDL induced target endothelial cells (EC) to bind monocyte but not neutrophil-like cells. Media collected from cocultures that had been incubated with LDL-induced monocyte migration into the subendothelial space of other cocultures that had not been exposed to LDL. In contrast, media from separate cultures of EC or smooth muscle cells (SMC) containing equal number of EC or SMC compared to coculture and incubated with the same LDL did not induce monocyte migration when incubated with the target cocultures. High density lipoprotein HDL, when presented to cocultures together with LDL, reduced the increased monocyte transmigration by 91%. Virtually all of the HDL-mediated inhibition was accounted for by the HDL2 subfraction. HDL3 was essentially without effect. Apolipoprotein AI was also ineffective in preventing monocyte transmigration while phosphatidylcholine liposomes were as effective as HDL2 suggesting that lipid components of HDL2 may have been responsible for its action. Preincubating LDL with beta-carotene or with alpha-tocopherol did not reduce monocyte migration. However, pretreatment of LDL with probucol or pretreatment of the cocultures with probucol, beta-carotene, or alpha-tocopherol before the addition of LDL prevented the LDL-induced monocyte transmigration. Addition of HDL or probucol to LDL after the exposure to cocultures did not prevent the modified LDL from inducing monocyte transmigration in fresh cocultures. We conclude that cocultures of human aortic cells can modify LDL even in the presence of serum, resulting in the induction of MCP-1, and that HDL and antioxidants prevent the LDL induced monocyte transmigration.

Antioxidants↗
PubMed1990

Prostaglandin E2, monocyte adherence and interleukin-1 in the regulation of human natural killer cell activity by monocytes.

Monocytes have previously been shown both to augment and suppress human natural killer (NK) cell activity depending upon the conditions. An interleukin-1/interleukin-2 (IL-1/IL-2)-dependent mechanism has been shown to be involved in the augmentative effect. In the current study, the role of the method of monocyte isolation was evaluated. Monocytes isolated by Percoll gradient centrifugation were ineffective for modulating NK activity, but monocytes isolated by adherence from most donors exhibited increased augmentation with increased interval of adherence (up to 1 h). However, monocytes isolated by adherence from certain donors reproducibly exhibited increased suppression with increased interval of adherence. The observation of augmentation was correlated with an increase in the balance between IL-1 production and prostaglandin E (PGE) production by the monocytes. The roles of PGE2 and IL-1 were therefore examined by mixing these cytokines with enriched null lymphocyte preparations in the absence or presence of monocytes in the NK assay system. The participation of PGE2 was further examined using monocytes treated with indomethacin (10(-6) M), and the participation of monocyte-membrane-bound IL-1 was evaluated using monocytes fixed with 1% paraformaldehyde. The results revealed that PGE2 production is involved in the suppression of human NK activity by human monocytes, and the functional balance between IL-1 and PGE2 determines whether suppression or augmentation is observed. The data of this and previous studies are consistent with the suggestion that membrane-associated IL-1 is the important IL-1 moiety for the augmentation of human NK activity by monocytes.

Adult↗
PubMed1990

IFN-alpha and IFN-gamma can affect both monocytes and tumor cells to modulate monocyte-mediated cytotoxicity.

IFN-alpha and IFN-gamma were found to enhance monocyte-mediated activity by acting on both tumor cells and monocytes. The addition of IFN-alpha or IFN-gamma enhanced the monocyte-mediated cytotoxicity of the human melanoma cell line, A375, as well as the human colon carcinoma cell line, HT-29. However, IFN-alpha generally induced more monocyte-mediated lysis of the A375 cells, whereas IFN-gamma induced more monocyte-mediated lysis of the HT-29 cells. These differences are, in part, due to the direct effects of the IFN on the tumor cells. Pretreatment of A375 cells with either IFN-alpha or IFN-gamma significantly enhanced their susceptibility to lysis by untreated monocytes. However, only IFN-gamma pretreatment of HT-29 cells enhanced the lysis of these cells by untreated monocytes. Differences were also observed in the activation of monocytes by IFN-alpha vs IFN-gamma with respect to their ability to induce soluble cytotoxic factors. We found that the addition of IFN-gamma and tumor cells (either the A375 or HT-29 cells) to monocytes induced TNF release, whereas IFN-alpha or IFN-gamma alone or IFN-alpha and tumor cells had no effect. Despite its presence, TNF did not appear to play a major role in the killing of either tumor cell line. However, inhibitors of H2O2-myeloperoxidase system suppressed both IFN-alpha- and IFN-gamma-induced cytotoxicity of the HT-29 cells. Thus IFN-alpha and IFN-gamma can induce both similar and distinct mechanisms of cytotoxicity in monocytes. In addition, both IFN types can increase the susceptibility of tumor cells to lysis by untreated monocytes, although sensitivity to IFN-alpha vs IFN-gamma may vary with different tumor cell lines. These differences observed between IFN-alpha and IFN-gamma on monocytes and tumor cells could have important implications for the clinical use of these cytokines.

Catalase↗