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PubMed1985

Oxidative metabolism in cord blood monocytes and monocyte-derived macrophages.

Little is known about phagocytosis-associated oxidative metabolism in mononuclear phagocytes from the human neonate. We investigated this phenomenon in monocytes from the cord blood of term newborn infants by measuring generation of superoxide anion (O2-) and hydroxyl radical (X OH) after stimulation with opsonized zymosan or phorbol myristate acetate. Production of these microbicidal oxygen metabolites by monocytes from neonates and healthy adult volunteers was equivalent. When cultured in the presence of the macrophage activator lipopolysaccharide or muramyl dipeptide, monocytes from neonates and adults differentiated into cells with the appearance of macrophages and with an enhanced capacity to release O2- compared with cells cultured in the absence of an activator. Monocyte-derived macrophages from neonates produced only slightly less O2- than did adult cells. Thus, unlike the cord blood neutrophil, which exhibits abnormalities in oxidative metabolism, the cord blood mononuclear phagocyte has a respiratory burst that is quantitatively comparable to that of the adult cell.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1996

Differentiation-associated toxin receptor modulation, cytokine production, and sensitivity to Shiga-like toxins in human monocytes and monocytic cell lines.

Infections with Shiga toxin-producing Shigella dysenteriae type 1 or Shiga-like toxin (SLT)-producing Escherichia coli cause bloody diarrhea and are associated with an increased risk of acute renal failure and severe neurological complications. Histopathological examination of human and animal tissues suggests that the target cells for toxin action are vascular endothelial cells. Proinflammatory cytokines regulate endothelial cell membrane expression of the glycolipid globotriaosylceramide (Gb(3)) which serves as the toxin receptor, suggesting that the host response to the toxins or other bacterial products may contribute to pathogenesis by regulating target cell sensitivity to the toxins. We examined the effects of purified SLTs on human peripheral blood monocytes (PBMn) and two monocytic cell lines. Undifferentiated THP-1 cells were sensitive to SLTs. Treatment of the cells with a number of differentiation factors resulted in increased toxin resistance which was associated with decreased toxin receptor expression. U-937 cells, irrespective of maturation state, and PBMn were resistant to the toxins. U-937 cells expressed low levels of GB(3), and toxin receptor expression was not altered during differentiation. Treatment of monocytic cells with tumor necrosis factor alpha (TNF-alpha) did not markedly increase sensitivity or alter toxin receptor expression. Undifferentiated monocytic cells failed to synthesize TNF and interleukin 1beta when treated with sublethal concentrations of SLT type I (SLT-I), whereas cells treated with 12-0-tetradecanoylphorbol-13-acetate acquired the ability to produce cytokines when stimulated with SLT-I. When stimulated with SLT-I, U-937 cells produced lower levels of TNF than PBMn and THP-1 cells did.

Adult↗
PubMed2002

Mice lacking monocyte chemoattractant protein 1 have enhanced susceptibility to an interstitial polymicrobial infection due to impaired monocyte recruitment.

Monocyte chemoattractant protein 1 (MCP-1) is an important chemokine that induces monocyte recruitment in a number of different pathologies, including infection. To investigate the role of MCP-1 in protecting a host from a chronic interstitial polymicrobial infection, dental pulps of MCP-1(-/-) mice and controls were inoculated with six different oral pathogens. In this model the recruitment of leukocytes and the impact of a genetic deletion on the susceptibility to infection can be accurately assessed by measuring the progression of soft tissue necrosis and osteolytic lesion formation. The absence of MCP-1 significantly impaired the recruitment of monocytes, which at later time points was threefold higher in the wild-type mice than in MCP-1(-/-) mice (P < 0.05). The consequence was significantly enhanced rates of soft tissue necrosis and bone resorption (P < 0.05). We also determined that the MCP-1(-/-) mice were able to recruit polymorphonuclear leukocytes (PMNs) to a similar or greater extent as controls and to produce equivalent levels of Porphyromonas gingivalis-specific total immunoglobulin G (IgG) and IgG1. These results point to the importance of MCP-1 expression and monocyte recruitment in antibacterial defense and demonstrate that antibacterial defense is not due to an indirect effect on PMN recruitment or modulation of the adaptive immune response.

Animals↗
PubMed1980

Monocytes in inflammatory bowel disease: absolute monocyte counts.

Using a cytochemical staining technique, peripheral blood monocytes have been precisely identified and enumerated in patients with inflammatory bowel disease and compared with healthy and disease control subjects. For ulcerative colitis there was a significant monocytosis, which was closely correlated with the total white cell count and with the activity of the disease. For patients with Crohn's disease, the peripheral blood monocyte count was also raised compared with that of the control groups, but the difference did not reach statistical significance. There was no correlation between the monocyte count in patients with Crohn's disease and the total white cell count or the disease activity. Some of the mechanisms that may influence the production and distribution of peripheral blood monocytes are discussed.

Adolescent↗
PubMed1997

Monocyte-macrophage differentiation induced by coculture of retinal pigment epithelium cells with monocytes.

Macrophages play an important role in proliferative vitreoretinopathy (PVR). Since macrophage maturation may be modulated by the local microenvironment, we determined the effect of retinal pigment epithelium (RPE) cells interacting with monocytes on macrophage maturation. The enriched monocyte fraction of peripheral blood mononuclear cells was cocultured with RPE cells. Cell-free supernatants conditioned during the culture periods 0-4 days (growing RPE cells) and 4-8 days (confluent RPE cells) were tested for their capacity to induce monocyte/macrophage differentiation of the promyelocytic cell line HL-60, which was measured by the expression of CD11c and CD14 and flow cytometry. RPE cells released factors that increased the CD14 expression on HL-60 cells in terms of percentage of positive cells (22.7% vs. control 10.4%). RPE-cell-conditioned supernatants had no effect on the CD11c expression. Monocytes secreted substances that increased the expression of CD11c (20.5% vs. control 9.1%; p = 0.003) and CD14 (31.6% vs. control 10.4%; p < 0.0001). Supernatants from cocultures increased the CD11c (19.8%) and CD14 expression (40.8%) to values that were similar to the sum of those of cell monocultures. Supernatants conditioned during the later culture had no effect on CD14 and CD11c expression. We conclude that invading monocytes and RPE cells could create an intraocular microenvironment that supports macrophage maturation during the initial stage of PVR.

CD11 Antigens↗
PubMed2004

Leukotriene B4 strongly increases monocyte chemoattractant protein-1 in human monocytes.

OBJECTIVE: Leukotriene B4 (LTB4), a product of the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, has been implicated in atherosclerosis. However, the molecular mechanisms for the atherogenic effect of LTB4 are not well understood. This study is to determine candidate mechanisms. METHOD AND RESULTS: Primary human monocytes were treated with LTB4 and the supernatant was analyzed for cytokine/chemokine production by an immuno-protein array. This analysis revealed a strong increase of the monocyte chemoattractant protein-1 (MCP-1), a proinflammatory cytokine. Follow-up analyses with MCP-1 enzyme-linked immunosorbent assay (for quantitation of MCP-1 protein) and real-time polymerase chain reaction (PCR) (for MCP-1 mRNA) demonstrated that LTB4 strongly induced expression of MCP-1 protein and mRNA in a time-dependent and dose-dependent fashion. This induction was effectively abolished by CP-105,696, an antagonist for the LTB4 receptor BLT1. Selective inhibitors of ERK1/2 or JNK MAPK effectively blocked the LTB4-induced MCP-1 production. Furthermore, LTB4 increased NF-[kappa]B DNA binding activity, which was blocked by CP-105,696. CONCLUSIONS: LTB4 strongly induces MCP-1 production in primary human monocytes. This induction is mediated through the BLT1 pathway increasing MCP-1 transcription. Activation of ERK1/2 or JNK MAPK is essential for this induction. The NF-[kappa]B activation may be involved in LTB4-increased MCP-1 expression. The LTB4-induced MCP-1 in human monocytes may play a critical role in the atherogenicity of LTB4.

Benzopyrans↗
PubMed1999

Monocyte chemoattractant protein-1 but not tumor necrosis factor-alpha is correlated with monocyte infiltration in mouse lipid lesions.

BACKGROUND: Apolipoprotein (apo)(a) transgenic mice and C57BL/6 mice fed a high fat diet develop similar-sized lipid lesions, but lesions in apo(a) mice are devoid of macrophages. We used this observation to identify which proinflammatory proteins might be involved in mediating monocyte recruitment during atherogenesis. METHODS AND RESULTS: Macrophage-deficient apo(a) transgenic mouse lesions contained similar levels of several different proinflammatory proteins, both adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]) and cytokines (tumor necrosis factor-alpha [TNF-alpha] and macrophage inflammatory protein-1alpha [MIP-1alpha]), similar to the macrophage-rich lesions of C57BL/6 mice. CONCLUSIONS: From this we conclude that ICAM-1, VCAM-1, TNF-alpha, and MIP-1alpha may all be necessary for vascular monocyte recruitment in vivo, but they cannot be sufficient. Monocyte chemoattractant protein-1 (MCP-1) protein was undetectable in the vessel wall taken from apo(a) transgenic mice fed a high fat diet compared with high expression in mice with lipid lesions (C57BL/6 and apoE knockout mice). Therefore elevated expression of MCP-1 but not TNF-alpha, MIP-1alpha, ICAM-1, or VCAM-1 is correlated with vascular macrophage accumulation. To test the hypothesis that monocyte infiltration during atherogenesis is MCP-1 dependent, it will be necessary to develop specific pharmacological inhibitors of MCP-1 activity.

Animals↗
PubMed2003

Homocysteine mediated expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human monocytes.

Homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) are major chemokines for leukocyte trafficking and have been identified in atheromatous plaques. MCP-1 and IL-8 have been found to express mainly by macrophages in human lesion. We undertook this study to determine whether Hcy could induce the secretion of chemokines from human monocytes and, if so, to explore the mediating mechanism. We found that clinically relevant levels of Hcy (10 to 1000 micromol/L) increased the protein secretion and mRNA expression as well as activity of MCP-1 and IL-8 in cultured primary human monocytes. These effects of Hcy were primarily mediated by reactive oxygen species (ROS) through NAD(P)H oxidase, because Hcy could upregulate the production of ROS and the inhibitors of protein kinase C, calmodulin, free radical scavengers, or NAD(P)H oxidase abolished Hcy-induced ROS production and MCP-1 and IL-8 secretion in these cells. Furthermore, the inhibitors of mitogen-activated protein kinase (p38 and extracellular signal-regulated kinase 1/2) and nuclear factor-kappaB or the activator of peroxisome proliferator-activated receptor gamma (PPARgamma) significantly decreased Hcy-induced MCP-1 and IL-8 secretion in these cells. These data indicate that pathophysiological levels of Hcy can alter human monocyte function by upregulating MCP-1 and IL-8 expression and secretion via enhanced formation of intracellular ROS originated from NAD(P)H oxidase source via calmodulin or protein kinase C signaling pathways and that Hcy-induced ROS subsequently activates mitogen-activated protein kinase (p38 and ERK1/2) and nuclear factor-kappaB in a PPARgamma activator-sensitive manner. Thus, activation of PPARgamma may become a therapeutic target for preventing Hcy-induced proatherogenic effects.

Antioxidants↗
PubMed1995

Mechanical strain induces monocyte chemotactic protein-1 gene expression in endothelial cells. Effects of mechanical strain on monocyte adhesion to endothelial cells.

Monocyte chemotactic protein-1 (MCP-1), a potent monocyte chemoattractant secreted by endothelial cells (ECs), is believed to play a key role in the early events of atherogenesis. Since vascular ECs are constantly subjected to mechanical stresses, we examined how cyclic strain affects the expression of the MCP-1 gene in human ECs grown on a flexible membrane base deformed by sinusoidal negative pressure (peak level, -16 kPa at 60 cycles per minute). Northern blot analysis demonstrated that the MCP-1 mRNA levels in ECs subjected to strain for 1, 5, or 24 hours were double those in control ECs (P < .05). This strain-induced increase was mainly serum independent, and MCP-1 mRNA level returned to its control basal level 3 hours after release of strain. Culture media from strained ECs contained approximately twice the MCP-1 concentration and more than twice the monocyte chemotactic activity of media from control ECs (P < .05). Pretreatment of collected media with anti-MCP-1 antibody suppressed such activity. Monocyte adhesion to ECs subjected to strain for 12 hours was 1.8-fold greater than adhesion to unstrained control ECs (P < .05). A protein kinase C inhibitor, calphostin C, abolished the strain-induced MCP-1 gene expression. In addition, cAMP- or cGMP-dependent protein kinase inhibitors (KT5720 and KT5823, respectively) partially inhibited such expression. Pretreatment with EGTA or the intracellular Ca2+ chelator BAPTA/AM strongly suppressed the strain-induced MCP-1 mRNA. Verapamil, a Ca2+ channel blocker, greatly reduced MCP-1 mRNA levels in both strained and unstrained ECs.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1997

Monocytes harboring cytomegalovirus: interactions with endothelial cells, smooth muscle cells, and oxidized low-density lipoprotein. Possible mechanisms for activating virus delivered by monocytes to sites of vascular injury.

Cytomegalovirus (CMV) infection and its periodic reactivation from latency may contribute to atherogenesis and restenosis. It is unknown how CMV is delivered to the vessel wall and is reactivated. We examined the following hypothesis: CMV, present in monocytes recruited to sites of vascular injury, is activated by endothelial cell (EC) or smooth muscle cell (SMC) contact and by oxidized low-density lipoproteins (oxLDLs). The CMV major immediate-early promoter (MIEP) controls immediate-early (IE) gene expression, and thereby viral replication. To determine whether elements of the vessel wall can activate CMV present in monocytes, we transiently transfected the promonocytic cell line HL-60 with a chloramphenicol acetyltransferase reporter gene construct driven by MIEP. MIEP activity increased 1.7 +/- 0.5-fold (P = .02) when the transfected HL-60 cells were cocultured with ECs, 4.5 +/- 1.5-fold when cocultured with SMCs (P = .03), and 2.0 +/- 0.5-fold (P = .01) when exposed to oxLDL. The combination of oxLDL and EC coculture increased MIEP activity over 7-fold. We also found that freshly isolated human monocytes, infected with endothelium-passaged CMV, were capable of transmitting infectious virus to cocultured ECs or SMCs. CMV-related progression of atherosclerosis or restenosis may, at least in part, involve monocyte delivery of the virus to the site of vascular injury, where the vascular milieu, ie, contact with ECs, SMCs, and oxLDL, can contribute to viral reactivation and/or replication by enhancing CMV IE gene expression. The virus may then infect neighboring ECs or SMCs, initiating a cascade of events predisposing to the development of atherogenesis-related processes.

Arteriosclerosis↗
PubMed2001

HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes.

The mechanism whereby HIV-infected cells transit from the bloodstream into tissues is not well defined. This phenomenon was addressed by studying the effects of HIV-1 Tat, a protein secreted by infected cells, on human lung microvascular endothelial cells (HMVEC-Ls). It was found that monocyte chemoattractant protein-1 (MCP-1) was released from HMVEC-Ls in a dose- and time-dependent manner after Tat treatment. MCP-1 is a potent beta-chemokine that recruits monocytes and T cells and promotes cell adhesion and transmigration across an endothelial monolayer. It was also observed that MCP-1 and the culture medium from Tat-treated HMVEC-Ls were chemotactic for CD14(+) monocytes from human peripheral blood and for THP-1, a promonocytic cell line used as a model system. To characterize the signaling pathways underlying the observed induction of MCP-1, HMVEC-Ls were treated with 2 different protein kinase inhibitors: PD98059, a MAP kinase inhibitor, and GF109203X, a protein kinase C (PKC) inhibitor. MCP-1 release was significantly reduced when PKC was inhibited, and slightly decreased when PI3 kinase was blocked; no effect on MCP-1 release was observed on MAP kinase inhibition. Similarly, transmigration of THP-1 cells was significantly impaired by the PKC inhibitor, but not by the other tested inhibitors. These data indicate that the HIV-1 Tat protein may act as a protocytokine by causing the release of MCP-1 from the endothelial monolayer, and thereby facilitating monocyte transmigration into tissues via a PKC signaling pathway.

Cell Culture Techniques↗
PubMed2001

Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages.

Rapamycin (Rapa), a recently introduced immunosuppressive drug, seems to be effective in preventing acute allograft rejection. Although its antiproliferative effect on T lymphocytes has been investigated extensively, its effect on the initiators of the immune response, the dendritic cells (DCs), is not known. Therefore, the effect of Rapa on monocyte- (mo-DCs) and CD34(+)-derived DCs in vitro but also on other myeloid cell types, including monocytes and macrophages, was examined. The present study shows that Rapa does not affect phenotypic differentiation and CD40L-induced maturation of mo-DCs. However, Rapa dramatically reduced cell recovery (40%-50%). Relatively low concentrations of Rapa (10(-9) M) induced apoptosis in both mo-DCs and CD34(+)-derived DCs, as visualized by phosphatidylserine exposure, nuclear condensation and fragmentation, and DNA degradation. In contrast, Rapa did not affect freshly isolated monocytes, macrophages, or myeloid cell lines. The sensitivity to Rapa-induced apoptosis was acquired from day 2 onward of mo-DC differentiation. Rapa exerts its apoptotic effect via a reversible binding to the cytosolic receptor protein FKBP-12, as demonstrated in competition experiments with FK506, which is structurally related to Rapa. Partial inhibition of Rapa-induced apoptosis was obtained by addition of ZVAD-fmk, which implies caspase-dependent and caspase-independent processes. The fact that Rapa exerts a specific effect on DCs but not on monocytes and macrophages might contribute to the unique actions of Rapa in the prevention of allograft rejection and other immune responses.

Antigen-Presenting Cells↗
PubMed2004

Abnormal monocyte recruitment and collateral artery formation in monocyte chemoattractant protein-1 deficient mice.

Monocyte chemoattractant protein 1 (MCP-1) has been shown to be effective for the stimulation of collateral artery formation in small and large animal models. The availability of a genetic knockout mouse enables evaluation of the importance of the role of MCP-1 in the natural course of collateral artery growth. In a total of 21 MCP-1 -/- as well as 13 of the appropriate genetic background controls ([129Sv/J X C57BI/6J]F1), a femoral artery ligation was performed. Subsequently, a polyethylene catheter, connected to an osmotic minipump, was inserted retrogradely into the occluded femoral artery with the tip pointing upstream. Using this technique, PBS (MCP-1 -/-: n = 13 and C57BI/6J: n = 13) or MCP-1 (JE; MCP-1 -/-: n = 8) was delivered intra-arterially. Seven days after ligation, determination of hind limb flow was assessed by controlled tissue perfusion using differently labeled fluorescent microspheres. MCP-1 -/- mice exhibited a reduction of hind limb flow of 32.9 +/- 9.2% of the unligated hind limb, compared with 55.4 +/- 6.8% in C57BI/6J mice (p<0.01). MCP-1 -/- mice that underwent a subsequent 'rescue' treatment with MCP-1 showed a restoration of flow to a level of 47.4 +/- 9.8% (p = NS compared with PBS-treated C57BI/6J). Specific immunohistochemical staining for monocytes (MOMA-2: MCP-1 -/-, n = 5 and C57BI/6J, n = 5) showed a reduced number of monocytes around developing collateral arteries in the MCP-1 -/- mice. In conclusion, our data show that the absence of MCP-1 causes a strong reduction in flow restoration after femoral artery occlusion, coinciding with a reduced monocyte attraction, emphasizing the central role of this chemokine in the multifactorial process of collateral artery formation.

Animals↗
PubMed2002

Monocyte chemoattractant protein-1 selectively inhibits the acquisition of CD40 ligand-dependent IL-12-producing capacity of monocyte-derived dendritic cells and modulates Th1 immune response.

Accumulating evidence indicates that monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, also displays immunoregulatory functions and may be involved in Th subset differentiation. In this study, we examined the effects of MCP-1 on the cytokine-driven differentiation of monocytes into dendritic cells (DCs), the most potent APCs for naive T cells. We found that DCs generated in the presence of MCP-1 displayed a markedly reduced production of IL-12 in response to CD40 ligand but not in response to Staphylococcus aureus stimulation in the presence or absence of IFN-gamma. The production of IL-10, a potent endogenous IL-12 inhibitor, was not affected by MCP-1. Whereas the inhibitory activity of MCP-1 on IL-12 production by monocytes was sensitive to pertussis toxin, its effects on DC differentiation were pertussis toxin resistant. MCP-1 did not affect the surface phenotype and T cell-stimulating activity of DCs, but most interestingly, naive T cells stimulated with MCP-1-primed DCs produced much less IFN-gamma but the same levels of IL-13. Taken together, our results indicated that MCP-1 modulates the differentiation of monocytes into DCs and may thereby inhibit Th1 cell development.

Adjuvants, Immunologic↗
PubMed2005

The role of p38 MAPK in rhinovirus-induced monocyte chemoattractant protein-1 production by monocytic-lineage cells.

Viral respiratory infections are a major cause of asthma exacerbations and can contribute to the pathogenesis of asthma. Major group human rhinovirus enters cells by binding to the cell surface molecule ICAM-1 that is present on epithelial and monocytic lineage cells. The focus of the resulting viral infection is in bronchial epithelia. However, previous studies of the cytokine dysregulation that follows rhinovirus infection have implicated monocytic lineage cells in establishing the inflammatory environment even though productive infection is not a result. We have determined that human alveolar macrophages and human peripheral blood monocytes release MCP-1 upon exposure to human rhinovirus 16 (HRV16). Indeed, we have found p38 MAPK activation in human alveolar macrophages within 15 min of exposure to HRV16, and this activation lasts up to 1 h. The targets of p38 MAPK activation include transcriptional activators of the MCP-1 promoter. The transcription factor ATF-2, a p38 MAPK substrate, is phosphorylated 45 min after HRV16 exposure. Furthermore, IkappaBalpha, the inhibitor of the transcription factor NF-kappaB, is degraded. Prevention of HRV16 binding was effective in blocking p38 MAPK activation, ATF-2 phosphorylation, and MCP-1 release. This is the first report of a relationship between HRV16 exposure, MCP-1 release and monocytic-lineage cells suggesting that MCP-1 plays a role in establishing the inflammatory microenvironment initiated in the human airway upon exposure to rhinovirus.

Activating Transcription Factor 2↗
PubMed2000

The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages.

Unstimulated monocytes rapidly undergo physiological changes resulting in programmed cell death (apoptosis) while stimuli promoting differentiation of these cells into macrophages were shown to inhibit apoptotic processes. In the present study, we report that the platelet-derived alpha-chemokine platelet factor 4 (PF4) induces the differentiation of monocytes into macrophages, as is evident from morphological changes as well as from the up-regulation of differentiation markers (carboxypeptidase M/MAX1 and CD71). Significant alterations of the phenotype were observed after 72 hours of culture in the presence of the chemokine and required a minimal concentration of 625 nmol/L PF4. PF4-induced macrophages were characterized by a lack of HLA-DR antigen on their surface but showed a strong increase in the expression of the CD28 ligand B7-2. Furthermore, PF4 stimulation prevented monocytes from undergoing spontaneous apoptosis during 72 hours of culture as determined in an annexin-V-binding assay. Although PF4 induced the secretion of relevant amounts of TNF-alpha, neutralizing antibodies directed against TNF-alpha or granulocyte-macrophage colony-stimulating factor (GM-CSF) did not revert PF4-induced rescue from programmed cell death, suggesting that PF4 exerts its antiapoptotic effects in a TNF-alpha- or GM-CSF-independent fashion. On the basis of these results, we propose a novel role for PF4 in the control of monocyte differentiation during an inflammatory process in vivo. (Blood. 2000;95:1158-1166)

Antibodies, Monoclonal↗
PubMed1999

Minimally modified low-density lipoprotein induces monocyte chemotactic protein-1 expression in vivo and a novel model for monocyte adhesion to arterial intima.

OBJECTIVE: To test whether minimally modified low-density lipoprotein (MM-LDL) can stimulate the arterial cells expressing MCP-1 in vivo and thus induce monocyte adherence to endothelium. METHODS: An animal model was constructed to study the function of MM-LDL in vivo. MM-LDL (600 micrograms/ml) was perfused into a segment of the femoral artery of rabbits (both ends of which were occluded with removable ligatures). After exposure to MM-LDL for 2 h, the arterial segments were taken out 6 or 18 h later. The arteries were subjected to in situ hybridization with 35S-labeled antisense monocyte chemotactic protein-1 (MCP-1) RNA probe and processed for scanning electron microscopy. RESULTS: The expression of MCP-1 mRNA of the arterial endothelial cells and smooth muscle cells were increased by 60% and 90% 6 h after perfusion and had a 3.2 folds and 1.6 folds increase 18 h after perfusion respectively as compared with control (arteries perfused with saline). There was also apparent monocyte adherence to the endothelium observed by scanning electron microscopy. CONCLUSION: MM-LDL can stimulate vascular cells in expressing MCP-1 mRNA and enhance monocyte adherence to endothelium in vivo.

Animals↗
PubMed2000

[Inhibition of monocytes adhesion to the intima of arterial wall by local expression of antisense monocyte chemotactic protein-1].

OBJECTIVE: To study the mechanism of monocyte recruitment in atherogenesis and to clarify the effect of monocyte chemotactic protein-1 (MCP-1) in this process. METHODS: Femoral arteries isolated from the rabbits which had been fed with a high cholesterol diet and locally perfused with MM-LDL within the artery beforehand, were used as the models. Antisense MCP-1cDNA was transferred into the arterial wall by injecting recombinant LNCX-anti-MCP-1/liposomal complex in the femoral sheath and the periarterial tissue. RESULTS: Expression of antisense MCP-1 mediated by recombinant LNCX plasmid/lipsomal complex gene transfer enabled to inhibit MCP-1 gene expression and adhesion of monocyte to the intima. CONCLUSION: MCP-1 plays an important role on the recruitment of monocytes in the arterial wall, which provides a potential clue in developing a gene therapy project for the prevention and treatment of atherogenesis.

Animals↗