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PubMed1994

Virulence factors determine attachment and ingestion of nonopsonized and opsonized Bordetella pertussis by human monocytes.

In the present study, the role of virulence factors in and the effect of opsonization on the interactions between Bordetella pertussis and human monocytes were investigated. The methods used facilitated the distinction between attachment and ingestion of bacteria by monocytes. Nonopsonized virulent B. pertussis cells attached to monocytes. Nonopsonized B. pertussis mutant strains deficient in filamentous hemagglutinin, fimbriae, or pertactin exhibited a reduced adherence to monocytes compared with that of their respective parental strains. Nonopsonized avirulent B. pertussis cells did not attach to monocytes. These results led to the conclusion that fimbriae and pertactin are involved in the adherence of nonopsonized virulent B. pertussis cells to monocytes and confirm the role of filamentous hemagglutinin in this process. In the absence of opsonins, about 40% of the monocyte-associated virulent B. pertussis cells were ingested. When B. pertussis cells were preopsonized with inactivated normal serum, about 50% of the monocyte-associated virulent B. pertussis cells were phagocytosed and about 80% of the monocyte-associated avirulent B. pertussis cells were ingested. These results indicate that virulence factors inhibit opsonin-mediated ingestion of B. pertussis by monocytes.

Antibodies, Bacterial↗
PubMed1997

Effects of gamma interferon and nitric oxide on the interaction of Mycobacterium avium subsp. paratuberculosis with bovine monocytes.

In this study, we examined the effects of recombinant bovine gamma interferon (rIFN-gamma) and nitric oxide (NO) on the interaction of M. avium subsp. paratuberculosis with bovine monocytes. Monocytes pretreated with rIFN-gamma exhibited slightly increased phagocytosis of M. avium subsp. paratuberculosis and modest inhibition of the intracellular growth of this microorganism. The number of viable intracellular bacilli decreased earlier in rIFN-gamma-pretreated monocytes than in control monocytes. After infection with M. avium subsp. paratuberculosis, NO was not constitutively released, but NO release from infected monocytes was induced by treatment with rIFN-gamma or with rIFN-gamma and lipopolysaccharide (LPS). Release of nitric oxide was inhibited by addition of N(G)-monomethyl-L-arginine; however, inhibition of nitric oxide did not alter the pattern of intracellular survival of M. avium subsp. paratuberculosis in rIFN-gamma-treated bovine monocytes. Although chemically generated nitric oxide killed M. avium subsp. paratuberculosis in a cell-free system in vitro, the amount of nitric oxide required was far greater than that released from infected monocytes stimulated with rIFN-gamma and LPS. Our data suggest that rIFN-gamma activates M. avium subsp. paratuberculosis-infected bovine monocytes to release nitric oxide but only modestly increases antimycobacterial activity of monocytes against this organism. This may be due, in part, to the fact that the amount of nitric oxide produced by rIFN-gamma-activated bovine monocytes is insufficient to kill intracellular M. avium subsp. paratuberculosis bacilli in vitro.

Animals↗
PubMed2000

alpha(v)beta(3) integrin and bacterial lipopolysaccharide are involved in Coxiella burnetii-stimulated production of tumor necrosis factor by human monocytes.

Coxiella burnetii, the agent of Q fever, enters human monocytes through alpha(v)beta(3) integrin and survives inside host cells. In addition, C. burnetii stimulates the synthesis of inflammatory cytokines including tumor necrosis factor (TNF) by monocytes. We studied the role of the interaction of C. burnetii with THP-1 monocytes in TNF production. TNF transcripts and TNF release reached maximum values within 4 h. Almost all monocytes bound C. burnetii after 4 h, while the percentage of phagocytosing monocytes did not exceed 20%. Cytochalasin D, which prevented the uptake of C. burnetii without interfering with its binding, did not affect the expression of TNF mRNA. Thus, bacterial adherence, but not phagocytosis, is necessary for TNF production by monocytes. The monocyte alpha(v)beta(3) integrin was involved in TNF synthesis since peptides containing RGD sequences and blocking antibodies against alpha(v)beta(3) integrin inhibited TNF transcripts induced by C. burnetii. Nevertheless, the cross-linking of alpha(v)beta(3) integrin by specific antibodies was not sufficient to induce TNF synthesis. The signal delivered by C. burnetii was triggered by bacterial lipopolysaccharide (LPS). Polymyxin B inhibited the TNF production stimulated by C. burnetii, and soluble LPS isolated from C. burnetii largely mimicked viable bacteria. On the other hand, avirulent variants of C. burnetii induced TNF production through an increased binding to monocytes rather than through the potency of their LPS. We suggest that the adherence of C. burnetii to monocytes via alpha(v)beta(3) integrin enables surface LPS to stimulate TNF production in THP-1 monocytes.

Bacterial Adhesion↗
PubMed2001

Interleukin-10 stimulates Coxiella burnetii replication in human monocytes through tumor necrosis factor down-modulation: role in microbicidal defect of Q fever.

Coxiella burnetii, an obligate intracellular bacterium, is the agent of Q fever. The chronic form of the disease is associated with the overproduction of interleukin-10 and deficient C. burnetii killing by monocytes. We hypothesized that the replication of C. burnetii inside monocytes requires a macrophage-deactivating cytokine such as interleukin-10. In the absence of interleukin-10, C. burnetii survived but did not replicate in monocytes. C. burnetii replication (measured 15 days) was induced in interleukin-10-treated monocytes. This effect of interleukin-10 is specific since transforming growth factor beta1 had no effect on bacterial replication. C. burnetii replication involves the down-modulation of tumor necrosis factor (TNF) release. First, interleukin-10 suppressed C. burnetii-stimulated production of TNF. Second, the addition of recombinant TNF to interleukin-10-treated monocytes inhibited bacterial replication. Third, the incubation of infected monocytes with neutralizing anti-TNF antibodies favored C. burnetii replication. On the other hand, deficient C. burnetii killing by monocytes from patients with chronic Q fever involves interleukin-10. Indeed, C. burnetii replication was observed in monocytes from patients with Q fever endocarditis, but not in those from patients with acute Q fever. Bacterial replication was inhibited by neutralizing anti-interleukin-10 antibodies. As monocytes from patients with endocarditis overproduced interleukin-10, the defective bacterial killing is likely related to endogenous interleukin-10. These results suggest that interleukin-10 enables monocytes to support C. burnetii replication and to favor the development of chronic Q fever.

Antigens, CD↗
PubMed1992

Dual regulation of silent and productive infection in monocytes by distinct human immunodeficiency virus type 1 determinants.

The regulation of human immunodeficiency virus type 1 infection and replication in primary monocytes was investigated by mutagenesis of recombinant proviral clones containing an env determinant required for the infectivity of monocytes. Virus replication was assayed by determination of reverse transcriptase activity in culture fluids and by recovery of virus from monocytes following cocultivation with uninfected peripheral blood mononuclear cells. Three virus replication phenotypes were observed in monocytes: productive infection, silent infection, and no infection. Incorporation of the monocytetropic env determinant in a full-length clone incapable of infection or replication in primary monocytes (no infection) conferred the capacity for highly efficient virus replication in monocytes (productive infection). Clones with the env determinant but lacking either functional vpr or vpu genes generated lower replication levels in monocytes. Mutation of both vpr and vpu, however, resulted in nearly complete attenuation of virus replication in monocytes, despite subsequent virus recovery from infected monocytes by cocultivation with uninfected peripheral blood mononuclear cells (silent infection). These findings indicate a central role for the "accessory" genes vpu and vpr in productive human immunodeficiency virus type 1 replication in monocytes and indicate that vpu and vpr may be capable of functional complementation.

Amino Acid Sequence↗
PubMed1996

Twin studies demonstrate a host cell genetic effect on productive human immunodeficiency virus infection of human monocytes and macrophages in vitro.

Biological and genetic variability is a prominent feature of human immunodeficiency virus (HIV) strains, especially in tropism, syncytium formation, and replicative capacity. To determine whether there were variable host cell effects on HIV replication in monocytes, three different strains of low-passage-number monocytotropic blood isolates of HIV and the laboratory-adapted strain Ba-L were inoculated into panels of adherent monocytes drawn from 44 different donors, and peak extracellular HIV p24 antigen titers were compared. The clinical HIV strains showed patterns of either moderate or low-level replication in most donor monocytes (20 to 4,000 pg/ml). However, within this range there was marked variation in peak titers in most donors. HIV type 1 Ba-L replicated in all donor monocytes to much higher levels with less variability (30 to 40 ng/ml). Furthermore, replication of 21 clinical blood-derived strains of HIV in blood monocytes and monocyte-derived macrophages (MDM) from pairs of identical twins and age-matched unrelated donors (URD) of the same sex were compared. In all of the seven pairs of identical twins, the kinetics of replication (measured by extracellular HIV p24 antigen) of panels of four clinical HIV type 1 isolates in monocytes were similar within pairs. However, marked and significant differences in kinetics of HIV production occurred within 10 of the 12 unrelated donor pairs (P = 0.0007). The remaining two URD pairs showed similar kinetic patterns, but only one pair had the same HLA-DR genotype. Similar results were observed with monocytes/MDMs obtained from a second bleed of the same donor. Hence, discordant patterns of HIV replication kinetics between URD monocyte pairs contrasted with concordant patterns in identical twin monocytes. These data strongly suggest a host cell genetic effect on productive viral replication in monocytes and MDMs. So far, no consistent genetic linkage of HIV replication pattern with HLA-DR genotype has been observed.

Adult↗
PubMed2002

Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy.

In vitro studies show that human immunodeficiency virus type 1 (HIV-1) does not replicate in freshly isolated monocytes unless monocytes differentiate to monocyte-derived macrophages. Similarly, HIV-1 may replicate in macrophages in vivo, whereas it is unclear whether blood monocytes are permissive to productive infection with HIV-1. We investigated HIV-1 replication in CD14(+) monocytes and resting and activated CD4(+) T cells by measuring the levels of cell-associated viral DNA and mRNA and the genetic evolution of HIV-1 in seven acutely infected patients whose plasma viremia had been <100 copies/ml for 803 to 1,544 days during highly active antiretroviral therapy (HAART). HIV-1 DNA was detected in CD14(+) monocytes as well as in activated and resting CD4(+) T cells throughout the course of study. While significant variation in the decay slopes of HIV-1 DNA was seen among individual patients, viral decay in CD14(+) monocytes was on average slower than that in activated and resting CD4(+) T cells. Measurements of HIV-1 sequence evolution and the concentrations of unspliced and multiply spliced mRNA provided evidence of ongoing HIV-1 replication, more pronounced in CD14(+) monocytes than in resting CD4(+) T cells. Phylogenetic analyses of HIV-1 sequences indicated that after prolonged HAART, viral populations related or identical to those found only in CD14(+) monocytes were seen in plasma from three of the seven patients. In the other four patients, HIV-1 sequences in plasma and the three cell populations were identical. CD14(+) monocytes appear to be one of the potential in vivo sources of HIV-1 in patients receiving HAART.

Amino Acid Sequence↗
PubMed2002

Role of endothelial MCP-1 in monocyte adhesion to inflamed human endothelium under physiological flow.

Monocyte chemoattractant protein-1 (MCP-1) is an essential chemokine involved in monocyte traffic across endo- and epithelial barriers both in vitro and in vivo. However, the contribution of endothelial MCP-1 signaling via its CCR2 receptor in monocyte adhesion to inflamed endothelium under flow is incompletely understood. A sensitive flow chamber assay was used to assess monocyte adhesion to TNF-alpha-activated primary human pulmonary artery endothelial cells (HPAEC) during physiological shear stress. Monocyte adhesion was markedly reduced ( approximately 45%) when HPAEC-derived MCP-1 was either neutralized with anti-MCP-1 mAb or inhibited by translational arrest of MCP-1 mRNA transcripts with MCP-1 antisense oligomers. Corresponding efficacy was observed for blockade of monocyte CCR2 receptor function by anti-CCR2 mAb or MCP-1 antagonists (9-76 analog). The impact of endothelial MCP-1 on monocyte-HPAEC adhesion occurred via beta(2)-integrin but not via beta(1)-integrin adhesion pathways. In this line, pretreatment of monocytes with MCP-1 but not RANTES provoked a rapid and transient neoepitope 24 expression on beta(2)-integrin alpha-chains, as analyzed by increased reporter mAb24 binding. Collectively, our data show an important cross talk of endothelial MCP-1 with monocyte CCR2 effecting monocyte firm adhesion to inflamed HPAEC under physiological flow conditions.

Antibodies, Monoclonal↗
PubMed1991

Monocyte kinetics in rabbits.

Previous studies of monocytes isolated from peripheral blood have suggested that the lung sequesters these cells and has an important role in monocyte kinetics. However, the lung also provides the first capillary bed encountered by these cells after intravenous injection. A major criticism of the previous reports is that the behavior of monocytes in the lung may be altered as a result of the isolation procedure. The present study addresses this question by comparing the distribution of isolated monocytes (87% pure) in various organs 10 min after they were injected into either the central venous or the arterial circulation. The data show that the extraction of monocytes on the first passage through the lung after intravenous injection was 86.5 +/- 1.5%. After the monocytes had circulated for 10 min, the lungs contained 35.5 +/- 2.5% of the cells after intravenous injection and 29.7 +/- 2.2% after intra-arterial injection (P greater than 0.05). The lung-to-blood recovery ratio after either intravenous or intra-arterial injection showed that the lung contained a marginating pool of monocytes that was five to seven times the size of the circulating pool. The retention of monocytes in a region of the lung was proportional to the regional erythrocyte transit time. The half-life of the radiolabeled monocytes in the circulation was approximately 25 h. We conclude that the lung contains a marginating pool of monocytes and speculate that they concentrate there in preparation for migration into the interstitium and air space of the lung.

Animals↗
PubMed1995

Interferon-gamma-induced downregulation of CD4 inhibits the entry of human immunodeficiency virus type-1 in primary monocytes.

We have previously shown that the treatment of monocytes with interferon-gamma (IFN-gamma) prior to exposure with human immunodeficiency virus type-1 (HIV) results in complete inhibition of HIV infection of monocytes. In the present report, we have extended this study to obtain information on the mechanism(s) underlying IFN-gamma-induced inhibition of HIV infection of monocytes. To examine the effect of IFN-gamma on HIV entry, the first event in the infectious cycle of the virus, we amplified HIV-gag sequences in the genomic DNA and RNA of IFN-gamma treated monocytes, and found no evidence for the presence of either proviral DNA or HIV RNA sequences. These results were consistent with the absence of intracellular HIV particles either in the latent or actively replicating state as determined by flow-cytometric analysis of these cells. Furthermore, no HIV-induced cytopathic effects, such as multinucleated giant cell formation or cell death, were observed in IFN-gamma-treated monocytes after their exposure to HIV. Stimulation of IFN-gamma-treated monocytes 6 days postinfection with tumor necrosis factor-alpha (TNF-alpha), which is known to augment HIV replication in the infected cells, did not result in the induction of the HIV indicating the absence of latent HIV infection in IFN-gamma-treated monocytes. Treatment of monocytes with IFN-gamma, TNF-alpha, or with a combination of the two agents which is known to induce antimicrobial free radical nitric oxide (NO2- in the murine system did not induce NO2- production human monocytes suggesting the antiviral activity of IFN-gamma to be independent of NO2(-)-mediated killing of HIV or HIV-infected monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

CD4 Antigens↗
PubMed2004

C-reactive protein does not directly induce tissue factor in human monocytes.

OBJECTIVE: It is generally assumed that C-reactive protein (CRP) induces synthesis of tissue factor (TF) in monocytic cells, thereby potentially initiating intravascular blood coagulation. We aimed to elucidate the mechanism of CRP-induced TF expression in monocytes and monocyte-derived macrophages (MDMs) in vitro. METHODS AND RESULTS: Monocytes were isolated from the blood of healthy donors and cultured with or without CRP or lipopolysaccharide (LPS) to study the time course of TF antigen and TF mRNA expression. Addition of 100 microg/mL CRP did not result in a significant increase in TF antigen (range: 9 to 163 pg/10(6) cells, n=11) and TF mRNA (relative number of TF transcripts; N(TF)=0.01 to 0.33), when compared with nonstimulated cells (TF antigen 7 to 46 pg/10(6) cells, N(TF)=0.01 to 0.13). Variation of CRP concentration and exposure time did not affect the TF response. Similar results were obtained in monocytes cultured in suspension and in MDMs. In contrast, TF was strongly induced by 10 microg/mL LPS (TF antigen 1125 to 6120 pg/10(6) cells, N(TF)=5.94 to 23.43). Cultured monocytes did express FcRgammaII, a putative CRP receptor, and addition of CRP induced a 7-fold increase in the production of monocyte chemoattractant protein-1 (MCP-1). Interestingly, CRP addition to peripheral blood mononuclear cells (PBMCs) did result in TF expression on monocytic cells. CONCLUSIONS: The absence of TF induction after incubation of purified monocytes with CRP indicates that CRP is unable to induce TF expression in monocytes and MDMs directly. The presence of CRP-induced TF expression in PBMCs suggests that CRP can induce TF indirectly, probably through cross-talk between cells.

Blood Cells↗
PubMed1998

Extracellular matrix modulates macrophage functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage traits by human peripheral blood monocytes in vitro.

Activated resident macrophages sustain atheroma, and a high macrophage content is associated with plaque vulnerability. Factors leading to differentiation and activation of these blood-derived cells remain largely uncharacterized. We investigated the contribution of interaction with collagen type I, the predominant component of atherosclerotic matrix, to differentiation and modulation of characteristic macrophage functions, including intracellular lipid accumulation and production of the typical matrix-degrading enzyme matrix metalloproteinase (MMP)-9. When used as an adhesion substrate for human peripheral blood monocytes in vitro, collagen type I increased monocyte differentiation, assessed by analysis of CD71 expression and cell spreading. Culturing on collagen type I doubled the number of differentiated monocytes at 24 hours (44.9+/-1.4% versus 18.4+/-1.7% on uncoated dishes, P<.001, n=3 independent experiments) and was a stronger stimulus for differentiation than phorbol myristate acetate, a known inducer of monocyte differentiation. The effect of substrate on intracellular accumulation of modified lipoproteins was assessed by quantitative confocal microscopy of monocytes incubated with fluorescent acetylated LDL. The collagen type I substrate also doubled the number of macrophages containing intracellular lipid and significantly increased the individual intracellular loading. Monocytes cultured on collagen type I also released more MMP-9 than did cells plated directly on plastic. The role of monocyte spreading was further assessed by treatment with colchicine, an inhibitor of cytoskeletal function, or with genistein, a nonspecific inhibitor of tyrosine kinases, shown to participate in cell adhesion. Cell spreading was inhibited in 72.3+/-6.7% of colchicine-treated and in 62.4+/-6.4% of genistein-treated monocytes (n=3, P<.01 in both cases). The same conditions also decreased secretion of MMP-9, and genistein reduced the number of acetylated LDL-containing cells (from 286+/-7 to 184+/-8 cells/mm2 with genistein, n=3, P<.001). Data showed a strong correlation (r>.98) between monocyte spreading on collagen type I and intracellular lipid accumulation. Our results indicate that interaction with vascular matrix may play an important role in differentiation of peripheral blood monocytes into resident lipid-laden macrophages, which act as central stimulators throughout the natural history of atheroma.

Arteriosclerosis↗
PubMed1999

Preactivated peripheral blood monocytes in patients with essential hypertension.

The purpose of this study was to investigate the possible involvement of human peripheral blood monocytes in the pathology of hypertensive disease. We determined the in vitro secretion patterns of proinflammatory cytokines obtained from isolated peripheral monocytes from normal controls and from hypertensive patients either after in vitro stimulation with angiotensin II (Ang II) with or without preincubation with an Ang II type 1 receptor antagonist (losartan) or after stimulation with lipopolysaccharide. Blood samples were obtained from 22 patients with essential hypertension (before any drug administration or after interruption of antihypertensive therapy) and from 24 normotensive healthy individuals used as a control group. Peripheral blood monocytes were isolated by density gradient centrifugation and plastic adherence. The state of monocyte activity was determined by the capacity to secrete tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6, (IL-6) either spontaneously or after stimulation. Cytokine concentrations were determined in culture supernatants by specific ELISA. Proinflammatory cytokine levels were assessed by semiquantitative reverse transcribed polymerase chain reaction. After stimulation with Ang II, the IL-1beta secretion of peripheral blood monocytes was significantly increased in hypertensive patients versus healthy individuals (P<0.05). In contrast, in monocytes preincubated with losartan before exposure to Ang II, IL-1beta secretion was diminished in both groups to comparable levels. The secretion of IL-1beta and TNF-alpha was significantly increased in peripheral blood monocytes from hypertensive patients versus healthy individuals after stimulation with lipopolysaccharide (TNF-alpha, P<0.02; IL-1beta, P<0.05). Upregulation of IL-1beta and TNF-alpha secretion in peripheral blood monocytes from hypertensive patients was also seen at the RNA level. Our results indicate preactivated peripheral blood monocytes in hypertensive patients. Ang II may be directly involved in the process of monocyte activation.

Adult↗
PubMed2001

Angiotensin II induces migration and Pyk2/paxillin phosphorylation of human monocytes.

Angiotensin (Ang) II has been shown to enhance the development of atherosclerotic lesions. Migration of monocytes is an early critical step in the atherosclerotic process. To elucidate mechanisms by which Ang II promotes atherogenesis, we investigated its effects on human monocyte migration. Ang II induced migration of human peripheral blood monocytes (HPBM) and human THP-1 monocytes at concentrations between 0.01 and 1 micromol/L, with a 3.6+/-0.6-fold induction in HPBM and a 4.8+/-0.9-fold induction in THP-1 cells at 1 micromol/L Ang II (both P<0.01 versus unstimulated cells). Addition of the Ang II receptor type 1 (AT1-R) antagonist losartan (1 to 100 micromol/L) suppressed Ang II-induced migration of HPBM and THP-1 monocytes in a dose-dependent manner, demonstrating an AT1-R-mediated mechanism. Ang II-directed migration was also blocked by the Src kinase inhibitor PP2 (10 micromol/L), by the extracellular-regulated protein kinase (ERK 1/2) inhibitor PD98059 (30 micromol/L), and by the p38-MAPK inhibitor SB203580 (10 micromol/L), indicating that Src, ERK 1/2, and p38 are all involved in Ang II-induced migration of HPBM and human THP-1 monocytes. The proline-rich tyrosine kinase 2 (Pyk2) and paxillin are 2 cytoskeleton-associated proteins involved in cell movement, phosphorylated by Ang II in other cell types, and abundantly expressed in monocytes. Ang II (1 micromol/L) induced Pyk2 and paxillin phosphorylation in human THP-1 monocytes, peaking after 10 minutes for Pyk2 with a 6.7+/-0.9-fold induction and after 2 minutes for paxillin with a 3.2+/-0.4-fold induction. Ang II-induced phosphorylation of both proteins was suppressed by losartan and the Src inhibitor PP2, whereas no effect was observed with PD98059 and SB203580. This study demonstrates a novel proatherogenic action of Ang II on human monocytes by stimulating their migration, through an AT1-R-dependent process, involving signaling through Src, ERK 1/2, and p38. Furthermore, the promigratory actions of Ang II in human monocytes are associated with the phosphorylation of 2 cytoskeleton-associated proteins, Pyk2 and paxillin.

Angiotensin II↗
PubMed2004

Monocyte count, but not C-reactive protein or interleukin-6, is an independent risk marker for subclinical carotid atherosclerosis.

BACKGROUND AND PURPOSE: Systemic inflammatory markers have been shown to predict future cardiovascular events, but whether they are associated with early atherosclerosis is uncertain. We investigated the relationship of inflammatory markers interleukin-6 (IL-6), high-sensitive C-reactive protein (hs-CRP), fibrinogen, monocyte count, and white cell count (WCC) with subclinical carotid atherosclerosis in a healthy community population. METHODS: B-mode carotid ultrasound was performed on 1111 randomly selected male and female subjects aged 27 to 77 years. Serum IL-6, hs-CRP, plasma fibrinogen, monocyte count, and WCC were measured on all subjects, along with conventional cardiovascular risk factors. RESULTS: Multivariate analysis showed that IL-6 (P<0.0001), fibrinogen (P=0.007), and monocyte count (P=0.001) were associated with carotid plaque formation in the whole population. Monocyte count remained associated independently with carotid plaque formation when adjusted further for conventional risk factors (odds ratio per SD increase in monocyte count 1.4; 95% CI, 1.13 to 1.73; P=0.002). IL-6 (P<0.0001), fibrinogen (P<0.0001), and monocyte count (P=0.04) were also associated with carotid intima-medial thickness (IMT) in the whole population. However, when adjusted further for conventional risk factors, none remained independently predictive of carotid IMT. Further analysis showed an age-monocyte interaction (P=0.03), with monocyte count being an independent predictor of carotid IMT in the older age group only (>53 years; P=0.003). CONCLUSIONS: In a healthy community population, monocyte count is a better independent predictor of common carotid IMT and plaque formation than IL-6, hs-CRP, fibrinogen, and WCC. Monocyte count may represent an inexpensive, easy-to-measure risk marker for subclinical carotid atherosclerosis.

Adult↗
PubMed2005

Monocyte count is a predictor of novel plaque formation: a 7-year follow-up study of 2610 persons without carotid plaque at baseline the Tromsø Study.

BACKGROUND AND PURPOSE: Activation of monocytes and differentiation into lipid-laden macrophages are fundamental events in generation of atherosclerotic lesions. There exist few data on monocyte activity and the risk for atherosclerosis. In this prospective population-based study, we examined whether monocyte count in blood is a predictor of future plaque formation in persons without pre-existing carotid atherosclerosis. METHODS: At baseline, we measured monocyte count, white cell count (WCC), fibrinogen, intima-media thickness (IMT), and traditional cardiovascular risk factors in 2610 men and women aged 25 to 82 years who on ultrasound had no plaque in their right carotid artery. After 7 years of follow-up, a new ultrasound screening was performed and the number of novel plaques was grouped as none, 1 plaque, and 2 or more plaques. RESULTS: In multivariate analysis, monocyte count, age, sex, total cholesterol, current smoking, systolic blood pressure, and IMT were independent predictors of novel plaque formation. No significant association was found between plaque formation and either WCC or fibrinogen. For 1 standard deviation (0.17x10(9)) increase in monocyte count, the risk of being in a higher plaque category increased by 18% (OR, 1.18; 95% CI, 1.08 to 1.29). In the highest monocyte quartile, the risk for having plaque compared with the lowest quartile was 1.85 (OR) (95% confidence interval, 1.41 to 2.43). Repeating the analysis without IMT did not change the monocyte estimate. Excluding subjects with cardiovascular disease and diabetes mellitus from analysis neither changed the monocyte estimate. CONCLUSIONS: Monocyte count is an independent predictor of future plaque formation in subjects without pre-existing carotid atherosclerosis.

Adult↗
PubMed2001

Raloxifene-mediated increase in matrix metalloproteinase-1 production by activated monocytes.

Matrix metalloproteinases (MMPs), proteolytic enzymes produced by monocytes, may contribute to atherosclerotic arterial wall remodeling and to plaque rupture. Because estrogen influences the synthesis of MMPs, we examined the effect of raloxifene, a selective estrogen receptor modulator, on monocyte MMP production. Human primary blood monocytes treated with raloxifene (10 micromol/L) in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor induced a 2- to 3-fold increase in MMP-1 production by monocytes. The enhancement of MMP-1 production by raloxifene in LPS-activated monocytes occurred through a cyclooxygenase-2- and prostaglandin E(2)-independent mechanism. Additionally, compared with monocytes acquired during the placebo phase, peripheral blood monocytes from 5 of 6 healthy postmenopausal women treated with raloxifene (60 mg daily for 1 month) in a clinical trial produced significantly higher levels of MMP-1 when the monocytes were activated with LPS. Furthermore, serum obtained during the raloxifene phase from 4 of these subjects, when added to control monocytes, significantly enhanced LPS-induced MMP-1 production compared with that from serum obtained during the placebo phase. In summary, raloxifene increases the production of MMP-1 in activated monocytes; this effect may be favorable in atherosclerotic arterial wall remodeling but unfavorable for plaque stability.

Arteriosclerosis↗
PubMed2005

Lung-marginated monocytes modulate pulmonary microvascular injury during early endotoxemia.

RATIONALE: The role of monocytes in acute endotoxemia has been ascribed to systemic release of mediators within the central circulation. Little is known about the potential role of "marginated" monocytes in regulating microvascular inflammatory signaling. OBJECTIVES: To investigate whether lung-marginated monocytes can locally activate pulmonary endothelial cells through cell contact-dependent interactions in early endotoxemia. METHODS: Mice were challenged with LPS to produce acute endotoxemia and pulmonary vascular injury. Adoptive transfer of ex vivo LPS-stimulated donor leukocytes to recipient mice was also performed to evaluate cell-associated inflammatory signaling between monocytes and endothelial cells within the lung. Cell suspensions from excised lungs were analyzed by flow cytometry for expression of tumor necrosis factor alpha (TNF-alpha) on monocytes and cell adhesion molecules on endothelial cells. RESULTS: Substantial numbers of monocytes rapidly marginated to the lungs after endotoxin challenge in mice, and lung-marginated monocytes expressed significantly higher levels of membrane TNF than circulating monocytes, due to higher TNF production by the marginated cells. Injection of activated wild-type donor leukocytes to wild-type or TNF receptor double knockout recipients demonstrated that lung-marginated monocytes can induce TNF-dependent upregulation of adhesion molecules on pulmonary endothelial cells. Injection of activated donor leukocytes from TNF knock-in mice that express uncleavable mutant membrane TNF also induced adhesion molecule upregulation in wild-type recipients without a systemic soluble TNF release. CONCLUSIONS: These results reveal a previously unacknowledged role for lung-marginated monocytes in early endotoxemia, exerting local, cell-associated TNF signaling within the pulmonary microcirculation, contributing to the evolution of pulmonary vascular injury.

Animals↗