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PubMed1983

Role of granulocytes and monocytes in experimental Staphylococcus epidermidis endocarditis.

The role of granulocytes and monocytes during the induction and course of Staphylococcus epidermidis endocarditis was investigated by the selective depletion of monocytes with the drug VP16-213 and of both granulocytes and monocytes with nitrogen mustard. The induction of endocarditis was influenced only by the depletion of monocytes: the 50% infective dose differed significantly, being 3.4 X 10(5) CFU in control rabbits and 3.4 X 10(4) CFU in the monocyte-depleted rabbits, whereas no significant differences were found between the latter and those depleted of both granulocytes and monocytes. Also, control rabbits injected with 10(6) or 10(7) CFU had a significantly higher incidence of sterile vegetations than did rabbits selectively depleted of granulocytes or monocytes. Compared with baseline values, mean monocyte numbers at the time of bacterial inoculation were significantly increased in control rabbits whose vegetations remained sterile, whereas this effect was not seen in rabbits whose vegetations became infected. The course of the endocarditis appeared to be significantly influenced by both granulocytes and monocytes. Comparison showed that a decrease of the same numbers of these cells per microliter of blood was accompanied for the monocytes by an approximately fourfold higher increase of the number of staphylococci in the vegetations. The correlation between the number of granulocytes and of monocytes on the one hand and the number of staphylococci in the vegetations on the other was not substantially influenced by the duration of the disease or the number of staphylococci injected to induce the endocarditis. The number injected proved to be significantly correlated with the number of staphylococci in the vegetations. In rabbits with numbers of CFU per gram of vegetation exceeding 10(7), blood cultures were usually positive. This finding applied rarely to control rabbits, but generally to drug-treated rabbits. In the latter animals a significant correlation between the number of staphylococci in the vegetations and in the circulation was found. We conclude that only monocytes have a measurable effect on the induction of Staphylococcus epidermidis endocarditis but during its course both granulocytes and monocytes keep the endocardial infection in check.

Animals↗
PubMed1983

Role of monocytes in polyclonal immunoglobulin production stimulated by sonicates of periodontally associated bacteria.

These studies were initiated to investigate monocyte regulation of polyclonal antibody responses of human peripheral blood lymphocytes stimulated by sonicates of periodontally associated bacteria. With pokeweed mitogen (PWM) as a positive reference, the role of monocytes in the peripheral blood lymphocyte response to Streptococcus sanguis and Wolinella HVS was examined by manipulating the number of monocytes and lymphocytes in culture. In comparison to PWM, optimal responses to the bacterial sonicates required very few monocytes (0.3% of the total cultured cells). Restoration of monocytes to physiological levels resulted in suppression of the response. PWM-stimulated responses were optimal at 5 to 15% monocyte content and were abolished after monocyte depletion. Individuals who were low responders or nonresponders to bacterial sonicates responded at normal levels after manipulation of monocyte concentration. Nonresponders produced normal levels of antibody when the monocyte concentration was reduced to 0.3% but were inhibited after monocyte reconstitution. The effects of monocyte concentration were tested over a wide dose range of bacterial sonicate and found to conform to the observed pattern throughout the dose range tested (10 to 1,000 micrograms/ml). The contrasting monocyte requirement of peripheral blood lymphocytes stimulated with PWM versus bacterial sonicates may reflect a quantitative difference in optimal macrophage concentration or may be due to a qualitative difference in lymphocyte-monocyte interactions in response to these activators.

Adult↗
PubMed1994

Defective antigen presentation by Mycobacterium tuberculosis-infected monocytes.

In this study we investigated the effect of an in vitro infection with Mycobacterium tuberculosis on the ability of human monocytes to present the soluble antigen tetanus toxoid to T cells. We observed that tetanus toxoid-specific T-cell proliferation was markedly reduced when monocytes were infected with large numbers (bacterium-to-monocyte ratio, 50:1) of both viable and heat-killed mycobacteria. The level of antigen-induced gamma interferon release also was decreased when M. tuberculosis-containing monocytes were used as antigen-presenting cells. However, mycobacterium-infected monocytes did not show or trigger suppressive activity, because the presence of mycobacterium-infected monocytes did not affect the T-cell response induced by tetanus toxoid-pulsed control monocytes. When M. tuberculosis-infected monocytes were fixed with paraformaldehyde, they were not able to serve as antigen-presenting cells even in the presence of untreated accessory monocytes. Moreover, the uptake of both viable and heat-killed M. tuberculosis cells reduced the expression of human leukocyte antigen DR on monocytes. With regard to accessory function, monocytes infected with large numbers of mycobacteria were less efficient as accessory cells than were control monocytes in cultures of T cells activated with pokeweed mitogen. These results indicate that infection with large numbers of M. tuberculosis cells impairs the ability of monocytes to process and/or present soluble antigen and to serve as accessory cells in T-cell activation.

Antigen Presentation↗
PubMed1998

Expanded CD14+ CD16+ monocyte subpopulation in patients with acute and chronic infections undergoing hemodialysis.

Infections are frequent complications in end-stage renal failure patients undergoing hemodialysis (HD), and peripheral blood monocytes are important cells in host defense against infections. The majority of circulating monocytes express high levels of lipopolysaccharide receptor antigen CD14 and are negative for the immunoglobulin Fcgamma receptor type III (CD16). We studied the occurrence of a minor subpopulation coexpressing low levels of CD14 together with CD16 in HD patients. In healthy controls CD14+ CD16+ monocytes account for 8% +/- 4% of CD14+ monocytes, with an absolute number of 29 +/- 14 cells/microl. In stable HD patients the CD14+ CD16+ subpopulation was significantly elevated (14% +/- 3%, or 66 +/- 28 cells/microl), while the number of CD14(++) monocytes (monocytes strongly positive for CD14) remained constant. In HD patients suffering from chronic infections a further rise in CD14+ CD16+ monocytes was observed (128 +/- 71 cells/microl; P < 0.01) such that this subpopulation constituted 24% of all blood monocytes. In contrast, numbers of CD14++ cells did not change compared to those for stable HD patients, indicating that the CD14+ CD16+ monocyte subpopulation was selectively expanded. During acute infections the CD14+ CD16+ cell subpopulation always expanded. A whole-blood assay revealed that CD14+ CD16+ monocytes exhibited a higher phagocytosis rate for Escherichia coli bacteria than CD14++ monocytes, underlining their role during host defense. In addition, CD14+ CD16+ monocytes expressed higher levels of major histocompatibility complex (MHC) class II antigens (HLA-DR, -DP, and -DQ) and equal amounts of MHC class I antigens (HLA-ABC). Thus, CD14+ CD16+ cells constitute a potent phagocytosing and antigen-presenting monocyte subpopulation, which is expanded during acute and chronic infections commonly observed in chronic HD patients.

Acute Disease↗
PubMed1998

Role of IL-10 in the crossregulation of prostaglandins and cytokines in monocytes.

In the present study we have focused mainly on the role of IL (interleukin)-10 in the crossregulation of prostaglandins and cytokines in human monocytes. We first determined the effects of tumor necrosis factor-alpha (TNF-alpha) and IL-10 on monocyte prostaglandin E2 (PGE2) production. Unstimulated monocytes constitutively produced a small but significant amount of PGE2 in the culture supernatants. Both TNF-alpha and lipopolysaccharide (LPS) caused a remarkable increase in monocyte PGE2 production. On the other hand, IL-10 alone was without effect on constitutive PGE2 production but drastically inhibited LPS-induced PGE2 production in monocytes. Moreover, this inhibitory effect of IL-10 was not simply attributable to its inhibition of TNF-alpha production in LPS-stimulated monocytes. Next, we determined the effect of PGE2 on TNF-alpha mRNA expression in monocytes. Treatment of monocytes with or without PGE2 showed no detectable TNF-alpha mRNA. Activation of monocytes by LPS resulted in a remarkable accumulation of TNF-alpha mRNA and PGE2 efficiently inhibited this expression. Finally, we determined the effect of PGE2 on IL-10 mRNA expression in monocytes. Similar to TNF-alpha mRNA, unstimulated monocytes showed no detectable IL-10 mRNA. Interestingly, PGE2 alone drastically induced IL-10 mRNA. Besides, activation of monocytes by LPS resulted in a remarkable accumulation of IL-10 mRNA, and PGE2 further enhanced this expression. These results indicate that TNF-alpha and PGE2 are key molecules for the induction of IL-10 in monocytes, and that IL-10, in turn, plays a crucial role in terminating the inflammatory cascade via downregulation of production of proinflammatory molecules including TNF-alpha and PGE2.

Cells, Cultured↗
PubMed2004

CD14+CD16+ monocytes in coronary artery disease and their relationship to serum TNF-alpha levels.

Monocytes play a central role in the inflammatory disease atherosclerosis. CD14+CD16+ monocytes are considered proinflammatory monocytes, as they have an increased capacity to produce proinflammatory cytokines, such as TNF-alpha, and are elevated in various inflammatory diseases. We hypothesized that patients with coronary artery disease (CAD) have increased levels of CD14+CD16+ monocytes, and that CD14+CD16+ monocytes are associated with inflammation markers. We investigated CD14+CD16+ monocytes in 247 patients with CAD and 61 control subjects using flow cytometry. In addition serum concentrations of TNF-alpha, IL-6, and Hs-CRP were assessed. Patients with CAD had higher levels of CD14+CD16+ monocytes than controls (13.6% versus 11.4%; p<0.001). Logistic regression analysis including quartiles of CD14+CD16+ monocytes showed that CD14+CD16+ monocytes were associated with prevalence of CAD (OR 4.9, 95% CI 2.5-19.1, for subjects in the fourth quartile in comparison to subjects in the first quartile). The association between CD14+CD16+ monocytes and CAD remained independently significant after adjustment for most potential confounders (OR 5.0, 95% CI 1.2-20.0). Serum concentrations of TNF-alpha were elevated in subjects within the highest quartiles of CD14+CD16+ monocytes (p=0.018). Our study showed that increased numbers of CD14+CD16+ monocytes are associated with coronary atherosclerosis and TNF-alpha. In accordance, recent animal studies suggest a possibly important role of these monocytes in the development of atherosclerosis.

Aged↗
PubMed2005

Exercise paradoxically modulates oxidized low density lipoprotein-induced adhesion molecules expression and trans-endothelial migration of monocyte in men.

Physical exercise can affect the risk of cardiovascular disease. Oxidized-low density lipoprotein (ox-LDL) promotes transendothelial migration (TEM) of monocyte, thereby accelerating the pathogenesis of atherosclerosis. This study investigated how exercise intensity affects monocyte/EC interactions under ox-LDL-mediated condition. Light- (LIE), moderate- (MIE) and high- (HIE) intensity exercise (i.e., 40%, 60%, and 80% VO2max, respectively) on a bicycle ergometer in 18 sedentary healthy men were performed on three separate occasions. Before and immediately after exercise, ox-LDL-promoted expressions of monocyte adhesion molecules and TEM of monocyte, as well as oxidation of LDL and amounts of soluble adhesion molecules in plasma were measured. Analytical results showed that (1) ox-LDL furthered monocyte L-selectin shedding and Mac-1 expression, and an attendant increase in TEM of monocyte, while treating the monocyte with Mac-1 antibody inhibited the ox-LDL-promoted TEM of monocyte; (2) under ox-LDL-treated condition, MIE increased monocyte Mac-1 and LFA-1 expressions, enhancing the TEM of monocyte, whereas HIE downregulated monocyte Mac-1 expression, suppressing the TEM of monocyte; (3) LIE decreased basal LFA-1 expression as well as basal and ox-LDL-promoted TEM of monocyte; and (4) MIE and HIE, but not LIE, elevated plasma ox-LDL level, while there were no significant changes in sL-selectin, sE-selectin, sICAM-1, and sVCAM-1 following these exercises. Therefore, we conclude that monocyte activation and subsequent TEM promoted by ox-LDL are changed by short-term exercise in an intensity-dependent manner. These findings provide a new insight into the may aid the development of suitable exercise intensity enable people to prevent early atherogenesis.

Adult↗
PubMed2006

Smoking-induced monocyte dysfunction is reversed by vitamin C supplementation in vivo.

OBJECTIVE: The role of antioxidants in preventing vascular disease remains controversial. Vascular endothelial growth factor (VEGF-A) is important for endothelial and monocyte function. This study investigated the negative effects of smoking on monocyte migratory responsiveness to VEGF-A and the usefulness of vitamin C to prevent smoking-induced monocyte dysfunction. METHODS AND RESULTS: The chemotactic response of isolated monocytes from a cohort of 17 non-smokers and 10 smokers toward VEGF-A was assessed. VEGF-A significantly stimulated the migration of monocytes in non-smokers; the monocytes from smokers failed to respond to VEGF-A. Repeated analysis after 2 weeks of vitamin C intake (2 g/d) showed a fully restored VEGF-A-induced monocyte migration in smokers. VEGF-A serum levels were not altered by vitamin C. VEGF-A-inducible kinase activity was intact in monocytes from smokers as assessed by in vitro kinase assay. Monocyte dysfunction can be mimicked in vitro by challenging monocytes with a range of reactive oxygen species (ROS). CONCLUSIONS: Stimulation of monocyte migration by VEGF-A was severely attenuated in smokers, and the deficit observed was surmounted by vitamin C supplementation. The negative effects of smoking on monocyte function may translate into adverse impacts on VEGF-A-dependent repair processes such as arteriogenesis. These results propose a causative role of oxidative stress in smoking-induced monocyte dysfunction.

Adult↗
PubMed1996

Monocyte- and cytokine-induced downregulation of angiotensin-converting enzyme in cultured human and porcine endothelial cells.

We investigated the effects of monocytes on endothelial cell (EC) ectoenzyme activity. Coculture of human aortic ECs with human monocytes (2 x 10(5) monocytes per 2-cm2 well) led to a decrease in EC angiotensin-converting enzyme (ACE) activity (64.5 +/- 3.5% of control) but not aminopeptidase N, aminopeptidase P, and 5'-nucleotidase activities. Similar results were obtained using human umbilical vein EC-human monocyte and porcine aortic EC-porcine monocyte cocultures. The decrease in ACE activity was monocyte concentration and coculture time dependent, reaching a maximum of 65% decrease in activity at 120 hours. Monocyte-mediated reduction in ACE activity did not require cell to cell contact, since exposure of ECs to conditioned medium from cocultures (CCCM) or from monocyte cultures (MCM) produced a decrease in ACE activity similar to that observed in EC-monocyte cocultures. Exogenously added tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 alpha, two known secretory products of monocytes, simulated the effects of monocytes on ACE activity. Western blot analysis revealed a decrease in the amount of ACE protein in TNF-alpha-treated and CCCM-treated ECs compared with control ECs. Both TNF-alpha and IL-1 alpha were present in CCCM and MCM but not EC-conditioned medium. Incubation of the cocultures with a mixture of neutralizing antibodies against TNF-alpha and IL-1 totally abolished the monocyte-induced decrease in ACE activity. In conclusion, monocytes decrease ACE activity in cultured ECs through the release of cytokines such as TNF-alpha and IL-1.

5'-Nucleotidase↗
PubMed1992

Increased oxygen species generation in blood monocytes of asthmatic patients.

Besides eosinophils, inflammatory processes in asthma are characterized by an infiltration of inflammatory cells, including mononuclear phagocytes, such as alveolar macrophages (AM) and blood monocytes, in the airways. Monocyte activation has been observed in the blood after exercise or allergen-induced asthma. Stimulated AM in chronic and stable asthmatic patients have been shown to release oxygen species. We thus investigated the intensity of the activation of monocytes from 18 asthmatic patients compared with 18 healthy subjects. Oxygen species release was analyzed for monocytes in suspension by chemiluminescence using a luminometer and for monocytes maintained in adherence using conventional assay and video imaging camera. Circulating blood monocytes in suspension from asthmatic patients and control subjects showed the same baseline free radical release. Monocytes in suspension from asthmatic patients were more stimulatable by PMA: specifically, monocytes release more H2O and peaks of O2-. are sooner; moreover, peaks of total free radical release are higher, and this plateau is sustained. Compared with monocytes from control subjects, those from asthmatic patients evaluated after adherence show a higher baseline for O2-. and higher total free radical release. Monocytes from asthmatic patients spontaneously release more O2-. over time in nonstimulated cells and release more O2-. with PMA stimulation; they show the same peak level total free radical release as those from control subjects after stimulation. SOD activity analysis on adherent monocytes was lower in asthmatic compared with control subjects. These data show that monocytes from asthmatic patients were activated compared with control monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acridines↗
PubMedDate not supplied

In vitro interleukin-8 production by monocytes treated with lithium chloride from breast cancer patients.

AIMS AND BACKGROUND: Since interleukin-8 (IL-8) has a suppressive effect on hematopoiesis, lithium induces leukocytosis and granulocytosis and mononuclear cells are defective in patients affected by neoplastic disease, we analyzed IL-8 production by monocytes obtained from patients with nonmetastatic breast cancer (BCaM0) and metastatic breast cancer (BCaM1) and the effect of lithium chloride (LiCl) on these cells. Lithium salt compounds are used to limit the degree and duration of neutropenia in patients receiving chemotherapy for cancer and acute leukemia. Lithium influences the hematopoietic system, which is known to be regulated by numerous cytokines including IL-8. METHODS: We selected three groups of subjects (15 per group): patients affected by BCaM0, BCaM1 and healthy donors (HD) matched for sex and age. IL-8 release was assessed in supernatants of lipopolysaccharide (LPS) and/or LiCl-treated monocyte cultures. RESULTS: Monocytes from BCaM1 released higher IL-8 levels than monocytes from BCaM0 (P <0.0001); the IL-8 levels of both groups were significantly higher (P <0.0001) than those of HD. In vitro LiCl treatment reduced IL-8 production by monocytes obtained from all subjects compared to the same cells when untreated or LPS treated. The suppressive effect of LiCl on IL-8 production by monocytes from breast cancer patients was particularly marked in monocytes from BCaM0 with respect to those from BCaM1. LPS treatment increased the IL-8 production more in BCaM1 monocytes than in BCaM0 monocytes. Moreover, combined LPS/LiCl treatment of monocytes significantly (p <0.0001) downregulated the release of IL-8 compared to treatment with LPS alone. CONCLUSIONS: Our data demonstrate that monocytes from BCaM0 release larger amounts of IL-8 than monocytes from BCaM0 and from HD. Lithium was able to downregulate IL-8 production by monocytes from different subgroups. Further studies are needed to clarify if the improvement of the hematopoietic system in vivo observed following lithium therapy could reside, at least in part, in the ability of lithium to downregulate this chemokine.

Adjuvants, Immunologic↗
PubMed1985

Multivariate analysis of the factors associated with the yield and purity of human monocyte isolation by countercurrent centrifugal elutriation (CCE).

Substantial variability in the purity and yield of human monocytes following countercurrent centrifugal elutriation (CCE) has been reported for some time; the factors influencing this variability have not been rigorously studied in the past. Utilizing 50 normal donors, we examined several dozen preprocedural variables possibly influencing 174 separate CCE experiments, and we determined the impact of these variables on the yield and purity of monocytes obtained following cytapheresis and CCE. Donor age was not correlated with CCE monocyte yield or purity; male gender correlated with higher monocyte purity following CCE purification. The major correlates of the yield and purity of monocytes obtained by CCE were the numbers and concentration of monocytes found in the leukocyte population entered into the elutriator apparatus. Fifty-eight percent of all donors gave a very consistent yield of monocytes by CCE, with a standard error from the mean of less than 15% over the 3 years of this study. All donors consistently gave fractions with a high percentage of monocytes, with the standard error of the mean CCE monocyte purity being less than 5% over the duration of the study. Thus, while the purity of monocytes collected by CCE is highly reproducible, the yield of monocytes by this procedure is somewhat less so. These monocyte purification endpoints are affected by a number of preprocedural variables centering mainly around the percentage, concentration, and total numbers of monocytes in the cytapheresis cell population.

Analysis of Variance↗
PubMed2002

Down-regulation of monocyte apoptosis by phagocytosis of platelets: involvement of a caspase-9, caspase-3, and heat shock protein 70-dependent pathway.

Monocytes interact and cross-talk with platelets in many settings including inflammation, hemostasis, or vascular disorders. During inflammatory diseases, there is a rapid targeting of monocytes and platelets to points of inflammation and endothelial injury, where they lie side-by-side. In this in vitro study, we investigated different interactions between monocytes and platelets and elucidated whether platelets might affect monocyte apoptosis. Freshly isolated human monocytes were rendered apoptotic by serum deprivation or CD95 ligation and cocultured with platelets. Monocyte apoptosis was determined by flow cytometry, TUNEL staining, DNA electrophoresis, and transmission electron microscopy imaging. We could show that monocyte apoptosis was highly suppressed when platelets were added to the cultures. Transmission electron microscopy depicted that monocytes completely ingested thrombocytes by phagocytosis. Blocking thrombocyte uptake by the phagocytosis inhibitor cytochalasin D abrogated the enhanced monocyte survival and led to high apoptosis levels. Monocyte survival was paralleled by down-regulation of caspase-9 and -3 and up-regulation of heat shock protein 70 during uptake of platelets. Platelet supernatants and contents of platelet granules were ineffective in altering monocyte senescence. Also, ingestion of latex beads or zymosan by monocytes was ineffective to mimic platelet-dependent rescue from apoptosis. In conclusion, this study shows that platelets can suppress apoptosis of monocytes by a specific phagocytosis-dependent process with further consequences for atherosclerotic or inflammatory conditions.

Apoptosis↗
PubMed2003

Short-time infusion of fish oil-based lipid emulsions, approved for parenteral nutrition, reduces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans.

Potential impact of omega-3 fatty acids, as contained in fish oil, on immunological function has been suggested because observations of reduced inflammatory diseases in Greenland Inuit were published. A fish oil-based lipid emulsion has recently been approved for parenteral nutrition in many countries. We investigated the influence of a short infusion course of fish oil-based (omega-3) vs conventional (omega-6) lipid emulsion on monocyte function. In a randomized design, twelve healthy volunteers received omega-3 or omega-6 lipid infusion for 48 h, with cross-over repetition of the infusion course after 3 mo. Fatty acid profiles, monocyte cytokine release and adhesive monocyte-endothelium interaction were investigated. Resultant omega-6 lipid emulsion increased plasma-free fatty acids including arachidonic acid, whereas the omega-3/omega-6 fatty acid ratio in monocyte membranes remained largely unchanged. It also caused a tendency toward enhanced monocyte proinflammatory cytokine release and adhesive monocyte-endothelium interaction. In contrast, omega-3 lipid emulsion significantly increased the omega-3/omega-6 fatty acid ratio in the plasma-free fatty acid fraction and in monocyte membrane lipid pool, markedly suppressing monocyte generation of TNF-alpha, IL-1, IL-6, and IL-8 in response to endotoxin. In addition, it also significantly inhibited both monocyte-endothelium adhesion and transendothelial monocyte migration, although monocyte surface expression of relevant adhesive molecules (CD11b, CD18, CD49 days, CCR2) was unchanged. Although isocaloric, omega-3 and omega-6 lipid emulsions exert differential impact on immunological processes in humans. In addition to its nutritional value, fish oil-based omega-3 lipid emulsion significantly suppresses monocyte proinflammatory cytokine generation and features of monocyte recruitment.

Adult↗
PubMed2001

CD14 expression on monocytes and TNF alpha production in patients with septic shock, cardiogenic shock or bacterial pneumonia.

OBJECTIVES: In patients with septic shock, circulating monocytes become refractory to stimulation with microbial products. Whether this hyporesponsive state is induced by infection or is related to shock is unknown. To address this question, we measured TNF alpha production by monocytes or by whole blood obtained from healthy volunteers (controls), from patients with septic shock, from patients with severe infection (bacterial pneumonia) without shock, and from patients with cardiogenic shock without infection. MEASUREMENTS: The numbers of circulating monocytes, of CD14+ monocytes, and the expression of monocyte CD14 and the LPS receptor, were assessed by flow cytometry. Monocytes or whole blood were stimulated with lipopolysaccharide endotoxin (LPS), heat-killed Escherichia coli or Staphylococcus aureus, and TNF alpha production was measured by bioassay. RESULTS: The number of circulating monocytes, of CD14+ monocytes, and the monocyte CD14 expression were significantly lower in patients with septic shock than in controls, in patients with bacterial pneumonia or in those with cardiogenic shock (p < 0.001). Monocytes or whole blood of patients with septic shock exhibited a profound deficiency of TNF alpha production in response to all stimuli (p < 0.05 compared to controls). Whole blood of patients with cardiogenic shock also exhibited this defect (p < 0.05 compared to controls), although to a lesser extent, despite normal monocyte counts and normal CD14 expression. CONCLUSIONS: Unlike patients with bacterial pneumonia, patients with septic or cardiogenic shock display profoundly defective TNF alpha production in response to a broad range of infectious stimuli. Thus, down-regulation of cytokine production appears to occur in patients with systemic, but not localised, albeit severe, infections and also in patients with non-infectious circulatory failure. Whilst depletion of monocytes and reduced monocyte CD14 expression are likely to be critical components of the hyporesponsiveness observed in patients with septic shock, other as yet unidentified factors are at work in this group and in patients with cardiogenic shock.

Antigens, CD↗
PubMed1999

Regulation of monocyte survival in vitro by deposited IgG: role of macrophage colony-stimulating factor.

IgG deposition at tissue sites characteristically leads to macrophage accumulation and organ injury. Although the mechanism by which deposited IgG induces tissue injury is not known, we have recently demonstrated that deposited IgG stimulates the release of IL-8 and monocyte chemoattractant protein-1 from normal human monocytes, which may drive inflammation. Since IgG also induces macrophage accumulation in these diseases, we hypothesized that deposited IgG protects monocytes from apoptosis. As an in vitro model of the effect of deposited IgG on monocyte survival, monocyte apoptosis was studied after FcgammaR cross-linking. Monocytes cultured on immobilized IgG, which induces FcgammaR cross-linking, were protected from apoptosis, whereas monocytes cultured with equivalent concentrations of F(ab')2 IgG or 50 times higher concentrations of soluble IgG, neither of which induces FcgammaR cross-linking, were not protected. Moreover, this protection was transferable, as supernatants from immobilized IgG-stimulated monocytes protected freshly isolated monocytes from apoptosis and contained functional M-CSF, a known monocyte survival factor. M-CSF mediated the monocyte survival induced by FcgammaR cross-linking, as neutralizing anti-human M-CSF Abs blocked the monocyte protection provided by either immobilized IgG or IgG-stimulated monocyte supernatants. These findings demonstrate a novel mechanism by which deposited IgG targets tissue macrophage accumulation through FcgammaR-mediated M-CSF release. This pathway may play an important role in promoting and potentiating IgG-mediated tissue injury.

Antigen-Antibody Complex↗
PubMed2001

Recruitment of labelled monocytes by experimental venous thrombi.

OBJECTIVE: Infusing monocytes that have been stimulated to produce fibrinolytic activators and factors that regulate cell proliferation, migration and maturation, might enhance venous thrombus resolution. The aim of this study was to determine the time course of infused monocyte recruitment into venous thrombus in an appropriate model of this disease. DESIGN AND METHODS: Thrombus was induced in the inferior vena cava of male Wistar rats using reduced flow (80-90% stenosis). The vessel wall was examined at 1hr by scanning electron microscopy. Resolving thrombi with surrounding vena cava were obtained at 1, 7, 14 and 21 days after induction (n = 8). Sections, taken at 0.5 mm intervals (10-15 sections per thrombus), were stained using haematoxylin, Martius Scarlet Blue and antibodies against monocytes, platelets and fibrin. Sections from human venous thrombi (n = 4) were similarly stained. The area occupied by monocytes (in relative pixel units, RPU) was determined using computer aided image analysis. Peripheral rat blood monocytes were extracted, fluorescently labelled and injected intravenously into 7 rats prior to thrombus induction, Vena cava with thrombus was harvested 1 h, 2, 3, 4, 7, 14 and 25 days after induction and their fluorescence measured. The fluorescent content of the caval wall and thrombus was analysed in greater detail at 2 and 25 days after thrombus induction (n = 4 at each time interval). RESULTS: Experimental thrombi were structurally similar to human thrombus and resolved within 14-21 days. Scanning electron microscopy showed minimal endothelial damage at 1 h with signs of early thrombus formation (platelet, red cell leukocyte and fibrin deposition). Neutrophils were the predominant leukocyte in the thrombus at 1 day, with monocytes making up only 0.3% (0.04% sem) of the area of the thrombus. There was a steady increase in thrombus monocyte content and by 21 days the percentage area of thrombus covered by monocytes had increased by over 35 fold to 11.5% (2.3% sem) (p <0.001). Initially, monocytes appeared around the edge of the thrombus and became more evenly distributed through the thrombus as resolution progressed. Labelled monocytes could be found in the circulation up to 1 week after infusion. The fluorescent content (RPU) of the thrombus increased over 25 days (mean RPU At 2 days 0.012, sem 0.005; mean RPU at 25 days 1.062, sem 0.252, p = 0.008). The number of labelled monocytes in the vessel wall peaked at 2 days and decreased thereafter. CONCLUSION: The structure of thrombi produced by this model was comparable to that of human venous thrombi. Endogenous and injected monocytes migrated into the thrombus during natural resolution, possibly via the vein wall. Monocyte targeting could therefore be used to develop novel treatments for venous thrombosis, with the aim of reducing post-thrombotic complications.

Animals↗
PubMed2001

[Expression of Fas on monocytes and the level of plasma soluble FasL in patients with chronic renal failure].

OBJECTIVE: The dysfunction of monocytes in uremic patients has been demonstrated to be associated with monocyte accelerated apoptosis. The study was conducted toelucidate the mechanisms by which monocyte apoptosis was induced. METHODS: Seven non-dialyzed chronic uremic patients and 18 hemodialysis (HD) patients were enrolled in the study. Fifteen healthy volunteers were selected as controls. The expression of Fas and Fas ligand (FasL) was examined by immunofluorescent staining and flow cytometer analysis. The levels of soluble FasL (sFasL) in plasma were analyzed by enzyme-linked immunosorbent assay (ELISA). The percentage of apoptotic cells in monocytes cultured in vitro with recombinant human FasL (rHu-FasL) was quantitated by DNA content analysis after extraction of the degraded DNA. Monocyte survival rate was analyzed by 5-diphenyl tetrazolium bromide (MTT) staining. RESULTS: Expression of Fas on monocytes was significantly higher in uremic and HD patients than that in healthy subjects. Higher levels of Fas expression were demonstrated on monocytes from HD as patients compared with those from non-dialyzed patients. There was no difference in monocyte Fas expression between pre- and post-dialysis session and between patients using polysulfone and cellulose dialyzer. There was no detectable FasL expression on monocytes from both uremic patients and healthy controls. Plasma sFasL could be detected in uremic and HD patients, but not in healthy controls. There was no significant difference in levels of plasma sFasL between non-dialyzed and HD patients, pre- and post-dialysis session, and patients treated with polysulfone and cellulose dialyzer. When monocytes were cultured in vitro with rHu-FasL for 2 hours, higher levels of apoptosis and lower survival rate were found in monocytes from HD patients as compared with those from healthy controls. CONCLUSION: The up-regulated expression of functional Fas on monocytes and the presence of sFasL in plasma may contribute to the accelerated apoptosis of monocytes seen in uremic patients.

Adult↗