Plasma Levels Of Monocyte Chemoattractant Protein-1 Research Articles

Monocyte chemoattractant protein-1 promoter polymorphism and plasma levels in alzheimer’s disease

BackgroundNeurodegenerative disorders such Alzheimer's disease (AD) are often characterized by senile plaques and neurofibrillary tangle. In addition, reactive astrogliosis, microglia activation and a chronic inflammation are found in AD brain. Activated microglia has been reported to express a large number of beta chemokines including monocyte chemoattractant protein-1 (MCP-1). The potential role of MCP-1 in AD pathogenesis is supported by the over expression of MCP-1 associated with an increase of amyloid deposition in transgenic mice. MCP-1 protein may be regulated by a single nucleotide polymorphism (SNP) occurring at position −2518 of the MCP-1 gene promoter. In this paper we correlated the A-2518G MCP-1 SNP distribution in three different populations: AD, control and MCI (mild cognitive impairment) population to evaluate whether this SNP might be a risk factor for AD or for MCI-AD conversion. MCP-1 plasma levels were also measured and correlated to the cognitive impairment (CIND) and AD risk.ResultsNo differences in genotype distribution and allele frequencies of A-2518G MCP-1 SNP among AD patients, MCI subjects and controls were observed even after APOEe4 variation adjustment with logistic regression. However in MCI subjects, followed up for two years, this SNP appears to influence the progression of the disease; being the G allele slightly more frequent in MCI patients that developed AD. MCP-1 plasma levels were different among CIND (cognitive impairment but no dementia), AD and controls. The MCP-1 A-2518G promoter polymorphism did not affect MCP-1 plasma levels within the three populations.ConclusionsMCP-1 G allele did not affect the risk of AD, but slightly influenced MCI conversion to AD and MCP-1 plasma levels were increased in subjects with preclinical AD.

Systemic immune system alterations in early stages of Alzheimer's disease

Immune activation and inflammation play significant roles in the pathogenesis of Alzheimer's disease (AD). To test whether AD patients showed systemic manifestations of inflammation, blood from 41 patients with early stages of AD and 31 aged-match elderly controls were evaluated. Cellular markers for monocyte/macrophage (MO) activation and CD8 T lymphocyte were increased in early AD patients. Expression of monocyte CCR2, the receptor for monocyte chemoattractant protein-1 (MCP-1), was decreased; however, plasma MCP-1 levels were significantly increased and were related to the degree of MO activation in AD. These findings suggest that AD pathogenesis may be influenced by systemic immunologic dysfunction and provides potential immunologic targets for therapeutic intervention.

CD36 in the periphery and brain synergizes in stroke injury in hyperlipidemia

Hyperlipidemia exacerbates ischemic stroke outcome and increases CD36 expression in the postischemic brain as well as in peripheral monocytes/macrophages. By exchanging bone marrow-derived cells between CD36-expressing and CD36-deficient mice, this study investigates the contribution of peripheral CD36 in comparison with that of brain CD36 to stroke pathology in hyperlipidemia. Following bone marrow transplantation, mice were fed a high-fat diet for 11 weeks and then subjected to ischemic stroke. Stroke outcome, expression of brain CD36, monocyte chemoattractant protein-1 (MCP-1), CCR2, and plasma MCP-1 levels were determined at 3 days postischemia. CD36 and CCR2 expression were also determined in splenocytes incubated with serum obtained from CD36-expressing or CD36-deficient mice. Infiltrating immune cells from the periphery are the major source of CD36 in the postischemic brain and contribute to stroke-induced brain injury. This CD36 effect was dependent on the modulation of MCP-1 and CCR2 expression in peripheral immune cells as well as CD36-expressing cells in the host brain. This study demonstrates that CD36 expressed in the periphery and brain synergize in ischemic brain injury through regulation of the MCP-1/CCR2 chemokine axis in hyperlipidemic conditions.

Monocyte chemoattractant protein-1 in schizophrenia: −2518A/G genetic variant and protein levels in Armenian population

Monocyte chemoattractant protein-1 (MCP-1) has been proposed as a contributory factor in pathophysiology of schizophrenia. The aim of the current study was to explore the possible association of the MCP-1−2518A/G genetic polymorphism and plasma levels of MCP-1 in patients with paranoid schizophrenia. The MCP-1−2518A/G (rs1024611) polymorphism and blood levels of MCP-1 in patients with paranoid schizophrenia and healthy subjects were evaluated and compared. One hundred and three chronic patients with paranoid schizophrenia treated with neuroleptics and 105 healthy subjects were genotyped using polymerase chain reaction with sequence-specific primers (PCR-SSP) and their MCP-1 plasma levels were measured by a solid-phase enzyme-linked immunosorbent assay (ELISA). When comparisons were made between patients and controls, the frequency of the MCP-1−2518*G minor allele (35% vs 23%, p=0.009, OR=1.77, 95% CI: 1.1–2.04) and also of the MCP-1−2518*G carriers (60% vs 40%, p=0.003, OR=2.27, 95% CI: 1.13–2.01) were higher in patients. The mean value of the MCP-1 plasma level in patients with schizophrenia was significantly higher than in controls. Interestingly, the patients with the GG genotype had the highest MCP-1 level (711.4±211.4pg/ml), followed by those with the AG genotype (472.1±135.8pg/ml) and AA (372.4±180.2pg/ml) homozygotes. In conclusion, we report here the association of the −2518A/G genetic polymorphism and increased plasma levels of MCP-1 with schizophrenia and nominate −2518*G minor allele as a risk factor for schizophrenia in Armenian population.

Values of biomarkers in the diagnosis of Coronary heart disease

ObjectiveTo clarify the value of plasma levels of high sensitivity C reactive protein (hs-CRP), soluble CD40 ligand (sCD40L), monocyte chemoattractant protein-1 (MCP-1), interleukin 8 (IL-8), interleukin 6 (IL-6), P-selectin, tissue-type...

Adenosine Diphosphate Receptor P2Y12-Mediated Migration of Host Smooth Muscle-Like Cells and Leukocytes in the Development of Transplant Arteriosclerosis

We have recently reported that platelet P2Y12 receptors may play a role in the development of transplant arteriosclerosis (TA). In the present study, we investigated the role of P2Y12 receptors on host-derived smooth muscle-like cells (SMLCs, including bone-marrow-derived SMLCs) and CD45+ leukocytes, both of which are believed to be associated with the development of TA, using P2Y12-deficient (KO) mice. Orthotopic carotid artery transplantation was performed from C3H/He (H-2k) donors into KO or wild-type (WT) recipient mice (129S:C57BL/6, H-2b). Grafts were harvested at 8 weeks after transplantation for histology. Plasma monocyte chemoattractant protein-1 (MCP-1) levels were analyzed with a kit. Cell migration was examined using a Boyden chamber system. The expression of MCP-1 messenger RNA was assessed by real-time polymerase chain reaction. Eight weeks after allotransplantation, KO recipient mice showed a significant reduction of luminal occlusion, host-derived SMLCs, CD45+ leukocytes, MCP-1+ cells in the grafts, and of plasma MCP-1 levels. In addition, the migration of host-derived SMLCs (including bone-marrow-derived SMLCs) and CD45+ leukocytes stimulated with adenosine diphosphate (ADP) or 2-methylthio-ADP (2MeSADP, a stable ADP analog) was significantly decreased in KO mice. There were no significant changes in MCP-1-induced cell migration between WT and KO mice. The low concentration of 2MeSADP plus MCP-1 significantly increased cell migration in WT but not KO mice. Furthermore, 2MeSADP-induced MCP-1 messenger RNA expression was significantly reduced in the cells of KO mice. Thus, the P2Y12-mediated migration of host-derived SMLCs and CD45+ leukocytes may play an important role in the development of TA, partly by MCP-1 pathways.

Periodic acceleration enhances release of nitric oxide in healthy adults

Periodic acceleration in the direction of the spinal axis through repetitive movements of a horizontal motion platform increases intravascular pulsatile shear stress. We hypothesized that periodic acceleration enhances release of nitric oxide (NO) in healthy subjects. We enrolled 8 healthy volunteers [39 ± 10 (SD) years]. Periodic acceleration was applied with the motion platform at a frequency of 2–3 Hz with approximately ± 0.25 g for 45 min in the fasting state. The procedure was repeated 20 times over 31 ± 10 days. Venous blood was sampled to determine plasma levels of NO, vascular endothelial growth factor (VEGF), tissue plasminogen activator (t-PA), and monocyte chemoattractant protein-1 (MCP-1) before and immediately after the first and 20th session. All the 8 subjects completed the 20 sessions without any adverse side effect. Periodic acceleration significantly increased the plasma levels of endproducts of NO from 17 ± 3 μmol/L at baseline and immediately after the first session to 24 ± 9 μmol/L immediately after the 20th session (each p < 0.05). Treatment with the motion platform did not change significantly the plasma levels of VEGF, t-PA, and MCP-1. These findings provide new evidence that periodic acceleration with the motion platform enhances release of NO.

Association between Plasma Monocyte Chemoattractant Protein-1 Levels and the Extent of Atherosclerotic Peripheral Artery Disease

Peripheral artery disease occurs at advanced ages and accounts for substantial cardiovascular morbidity and mortality. Monocyte chemoattractant protein-1 (MCP-1), a member of the cysteine-cysteine family of chemokines, is one of the cytokines involved in the pathogenesis of atherosclerosis and is also known as cysteine-cysteine chemokine ligand 2 (CCL2). The aim of the current study was to investigate the association between the extent of atherosclerotic peripheral artery disease (PAD) and the increase in MCP-1 level. Eighty consecutive patients who had undergone peripheral angiography for suspected PAD were included. Of these patients, 48 (60%) had hypertension, 23 (28.8%) had type 2 diabetes mellitus, 39 (48.8%) had a family history of coronary artery disease, 23 (28.8%) were cigarette smokers, and 42 (52.5%) had hypercholesterolemia. Angiography revealed that the peripheral arteries of the lower extremity were normal in 41 (51.3%) patients, whereas 39 (48.7%) patients had varying degrees of PAD. The patients were queried regarding age, gender, and atherosclerotic risk factors. The plasma MCP-1 levels were significantly lower in the patients without PAD than those in the patients with PAD (172.27 ± 38.05 pg/mL vs. 200.87 ± 39.31 pg/mL, p = 0.001). Moreover, as the severity of PAD increases, MCP-1 levels also increase. Thus, the plasma MCP-1 level can be used in the diagnosis of PAD and in determining the extent of atherosclerotic PAD of the lower extremities, as in determining the extent of coronary artery disease.

Fluoxetine treatment for major depression decreases the plasma levels of cytokines

Elevated levels of pro-inflammatory biomarkers have been reported in major depressive disorder (MDD). The aim of this study is to investigate the plasma levels of interleukin-18 (IL-18), macrophageinflammatory protein-1α (MIP-1α), monocyte chemoattractant protein 1 (MCP-1), stromal cell derived factor-1 (SDF-1), and regulated upon activation, normal T cell expressed and secreted (RANTES) in patients with MDD before and after eight week treatment of fluoxetine hydrochloride in comparison with normal controls. All subjects were assessed before and after treatment with the Hamilton Depression Rating Scale (HDRS). Our results showed that the symptoms of forty healthy controls and thirty-four patients with MDD were correlated with their plasma levels of IL-18, MIP-1α, MCP-1, SDF-1α, and RANTES. The levels of all five cytokine of patients with MDD were significantly decreased after treatment. However, the levels remained significantly higher than those of the healthy controls (p<0.001). In the seven depressed subjects whose HDRS score fell to below seven after antidepressant therapy comparing with those subjects whose HDRS score larger than seven, the mean levels of IL-18 (p=0.01) and SDF-1α(p<0.05) were significantly lower. Conversely, higher levels of cytokines correlated with a persistently increased severity of symptoms, as measured by the HDRS scores. In conclusion, these findings suggest that MDD is associated with activation of the immune system, and the antidepressant effect of fluoxetine may be mediated in part through its anti-inflammatory effects. Key words : Fluoxetine hydrochloride, major depression, cytokine, chemokine, inflammation.

Urinary monocyte chemoattractant protein-1 correlates with disease activity in lupus nephritis

Monocyte chemoattractant protein-1 (MCP-1) has a pathogenic role in murine lupus nephritis (LN). We recruited 25 pediatric and adolescent systemic lupus erythematosus (SLE) patients from our lupus clinic [13 (52%) patients with LN and 12 (48%) lupus non-nephritis patients] and evaluated their urinary and plasma MCP-1 levels compared to adult and childhood controls. The median age and SLE disease duration of patients were 14.4 and 5.5 years, respectively. LN patients had a higher median renal (p=0.01) British Isles Lupus Assessment Group (BILAG) index, with a tendency for higher total BILAG scores (p=0.2). There were significantly increased urinary MCP-1 levels in the LN patients compared to healthy controls (p<0.001) whose values were significantly higher than lupus non-nephritis children (p<0.004). Urinary MCP-1 levels correlated well with total BILAG scores (r=0.82, p=0.04). There were no differences in plasma MCP-1 levels between SLE patient groups and pediatric controls, although the levels in the childhood controls were elevated compared to those of the adult controls (p<0.04). These results provide evidence of increased urinary--but not plasma--MCP-1 levels in children with LN, which correlates well with SLE disease activity as measured by the BILAG index.

Dietary intervention-induced weight loss decreases macrophage content in adipose tissue of obese women

Accumulation of adipose tissue macrophages (ATMs) is observed in obesity and may participate in the development of insulin resistance and obesity-related complications. The aim of our study was to investigate the effect of long-term dietary intervention on ATM content in human adipose tissue. We performed a multi-phase longitudinal study. A total of 27 obese pre-menopausal women (age 39 ± 2 years, body mass index 33.7 ± 0.5 kg m(-2)) underwent a 6-month dietary intervention consisting of two periods: 4 weeks of very low-calorie diet (VLCD) followed by weight stabilization composed of 2 months of low-calorie diet and 3 to 4 months of weight maintenance diet. At baseline and at the end of each dietary period, samples of subcutaneous adipose tissue (SAT) were obtained by needle biopsy and blood samples were drawn. ATMs were determined by flow cytometry using combinations of cell surface markers. Selected cytokine and chemokine plasma levels were measured using enzyme-linked immunosorbent assay. In addition, in a subgroup of 16 subjects, gene expression profiling of macrophage markers in SAT was performed using real-time PCR. Dietary intervention led to a significant decrease in body weight, plasma insulin and C-reactive protein levels. After VLCD, ATM content defined by CD45+/14+/206+ did not change, whereas it decreased at the end of the intervention. This decrease was associated with a downregulation of macrophage marker mRNA levels (CD14, CD163, CD68 and LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1)) and plasma levels of monocyte-chemoattractant protein-1 (MCP-1) and CXCL5 (chemokine (C-X-C motif) ligand 5). During the whole dietary intervention, the proportion of two ATM subpopulations distinguished by the CD16 marker was not changed. A 6-month weight-reducing dietary intervention, but not VLCD, promotes a decrease in the number of the whole ATM population with no change in the relative distribution of ATM subsets.

Relationship of monocyte chemoattractant protein 1 (MCP-1) with insulin resistance and body mass index, but not with thermogenetic hormones in obesity

Monocyte chemoattractant protein 1 (MCP-1) has been implicated in the recruitment of monocytes to atheroma and of monocytes and macrophages to adipose tissue. The aim of the study was to examine whether MCP-1 levels are associated independently with the main thermogenetic hormones (serum TSH and thyroid hormones and 24-h urinary catecholamines) and insulin resistance in a population mainly represented by overweight and obese women. A cohort of 100 consecutive euthyroid women, aged 18–65 years, and with a wide range of BMI, was examined. Central fat accumulation (indirectly measured by waist circumference), fasting MCP-1 plasma levels, and TSH, FT3, FT4, insulin, glucose, and lipid (cholesterol, HDL-cholesterol and triglyceride) serum concentrations, and 24-h urinary catecholamines were measured. Insulin resistance was estimated by homeostasis model assessment (HOMAIR). MCP-1 levels were directly associated with BMI (p < 0.001), waist circumference (p < 0.001), insulin (p < 0.001), HOMAIR (p < 0.001), diastolic blood pressure (DBP) (p < 0.001), systolic blood pressure (SBP) (p < 0.001), triglycerides (TG) (p < 0.05), and 24-h urinary noradrenaline (p < 0.05), and negatively correlated with HDL-cholesterol (p < 0.01). When a multiple regression analysis was performed with MCP-1 as the dependent variable, and only parameters showing a significant univariate association with MCP-1 were considered as the independent variables, MCP-1 maintained an independent positive association with insulin (p < 0.01), and DBP (p < 0.05). When insulin was replaced by HOMAIR in the regression analysis, MCP-1 maintained an independent positive association with HOMAIR (p < 0.05), DBP (p < 0.05), and BMI (p < 0.05). In conclusion, this study suggests that insulin, BMI, and diastolic blood pressure cooperate independently in increasing MCP-1 levels, whereas thyroid hormones and catecholamines have no apparent influence on this chemokine.

Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease

ObjectiveTo document the expression patterns of various matrixins, cytokines and angiogenic factors in plasma to assess their involvement in the pathogenesis of moyamoya disease (MMD).MethodsThis study included plasma samples from...

Low plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF) in patients with alpha1-antitrypsin deficiency-related fibromyalgia

Abnormalities in blood inflammatory markers have been associated with clinical manifestations and the pathogenesis of the fibromyalgia syndrome (FMS); a relationship between inherited alpha1-antitrypsin deficiency (AATD) and FMS has also been recently raised. In this study, plasma levels of inflammatory markers in FMS patients with and without AATD have been investigated. Blood samples from 138 age-matched females (79 FMS) and 59 general population (GP), with normal MM [n = 82 (59.4%)] and with MS, MZ, SZ, and ZZ AATD genotypes [n = 56 (40.6%)], were analyzed by ELISA for monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFalpha), soluble TNFalpha receptors I and II, interleukin-8, and vascular endothelial growth factor (VEGF). Plasma levels of MCP-1, VEGF, and TNFalpha were significantly lower in FMS and GP subjects with AATD compared with those with normal MM-AAT genotypes. Moreover, plasma levels of MCP-1, VEGF, and TNFalpha were lower in AATD subjects with FMS than in those without FMS (P = 0.000, 0.000, and 0.046, respectively). No statistical differences were found for the other substances measured. Furthermore, a logistic regression model based on plasma MCP-1 cutoff value of <or=130 pg/ml allowed us to discriminate between FMS and GP subjects with a sensitivity of about 93% and a specificity of 79%. Low plasma levels of MCP-1, VEGF, and TNFalpha are related to AATD, although more markedly in FMS patients. Thus, hypotheses considering FMS as an inflammatory condition related to high plasma levels of inflammatory biomarkers cannot be supported.

Plasma monocyte chemoattractant protein-1 as risk marker in type 2 diabetes mellitus and coronary artery disease in North Indians

The chemokine monocyte chemoattractant protein-1 (MCP-1) is implicated in chronic inflammation, insulin resistance and atherosclerosis. The present study was designed to explore the relation of plasma levels of MCP-1 to disease pathology in type 2 diabetes and coronary artery disease (CAD) patients. Fasting plasma venous samples were taken from 162 subjects divided into four groups: Patients with type 2 diabetes mellitus and CAD (n=41), type 2 diabetes patients without CAD (n=50), CAD patients with no history of diabetes (n=41) and healthy controls (n=30). Coronary risk factors such as body mass index, percentage body fat, waist/hip ratio, blood pressure and physical activity were measured using standard procedures. Plasma MCP-1 was quantitatively estimated by sandwich enzyme-linked immunoabsorbent assay (ELISA). Significant differences were observed for MCP-1 levels, percent body fat, body mass index, waist/hip ratio, systolic and diastolic blood pressure amongst the groups. MCP-1 concentration was significantly correlated with diabetes duration (p<0.001), body mass index (p<0.01), waist/hip ratio (p<0.01), systolic blood pressure (p<0.01), percentage body fat (p<0.01) and physical activity level (p<0.001). MCP-1 might serve as a marker for CAD, and its association with CAD is mainly driven by traditional coronary risk factors.

Effects of pitavastatin on monocyte chemoattractant protein-1 in hyperlipidemic patients

The effects of statins on platelet activation markers, chemokines and adiponectin, were investigated in 135 patients with hyperlipidemia. Of the 135 hyperlipidemic patients, 63 were allocated to the simvastatin group, treated with simvastatin at the dose of 10 mg daily, and the remaining 72 were allocated to the pitavastatin group, treated with pitavastatin at the dose of 2 mg daily. Plasma levels of platelet-derived microparticles (PDMP), cell adhesion molecules (sCD40L and sP-selectin), chemokines [monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normally T-cell expressed and secreted] and adiponectin were measured at the baseline and after 6 months of treatment in both the groups. In addition, we carried out a basic study to investigate the MCP-1-dependent induction of tissue factor expression on a histiocytic cell line (U937 cells). The plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 were higher, whereas those of adiponectin were lower, in the hyperlipidemic patients than in the normolipidemic controls. Plasma PDMP and sCD40L were positively correlated, whereas plasma adiponectin was negatively correlated, with the plasma levels of MCP-1. No significant differences in the plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 measured before and after treatment were observed in either the simvastatin or pitavastatin group. A significant increase of the plasma adiponectin levels was observed after 6 months of treatment with pitavastatin but not after an equal duration of treatment with simvastatin. When pitavastatin-treated patients were divided into two groups according to the adiponectin response to pitavastatin treatment, significant decreases of the plasma MCP-1, PDMP and sCD40L levels were observed after pitavastatin treatment in the responder group. In the aforementioned basic study, MCP-1 by itself did not induce the expression of tissue factor on the U937 cells. However, the recombinant sCD40L-induced expression of tissue factor on U937 was enhanced by the addition of MCP-1. These findings suggest that PDMP, sCD40L and MCP-1 may participate in the development of atherothrombosis in patients with hyperlipidemia and that pitavastatin may exert an adiponectin-dependent antiatherothrombotic effect in hyperlipidemic patients.

The effect of edaravone on plasma monocyte chemoattractant protein-1 levels in patients with acute myocardial infarction

Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the pathogenesis of acute coronary syndrome. We have recently demonstrated that the administration of edaravone before reperfusion attenuated reperfusion injury in patients with acute myocardial infarction (AMI). Plasma MCP-1 levels were measured in 45 consecutive patients with AMI (edaravone group, n=25; control group, n=20). In the edaravone group, 30 mg edaravone was intravenously infused just before reperfusion. Plasma samples were obtained before and at 24h, 3, 5, 7, and 14 days after reperfusion. Cardiovascular events were defined as cardiac death, subacute thrombosis, or fatal arrhythmia. Heart failure requiring rehospitalization was evaluated at 12 months after reperfusion. Plasma MCP-1 levels were not different between the two groups before reperfusion. Compared with the placebo group, the edaravone group had statistically lower maximum creatine kinase-MB levels (218±31 IU/l versus 145±21 IU/l, p<0.05) and plasma MCP-1 levels on day 3 after reperfusion (873±118 pg/ml versus 516±66 pg/ml, p<0.05). Heart failure requiring rehospitalization occurred in four patients in the control group, but did not occur in the edaravone group (p<0.05). At 12 months after reperfusion, left ventricular ejection fraction was statistically higher in the edaravone group than in the control group (62±2% versus 54±3%, p<0.05). Edaravone suppressed plasma MCP-1, improved left ventricular ejection fraction, and reduced rehospitalization due to heart failure. Suppression of plasma MCP-1 level by edaravone might induce better prognosis for AMI patients.

Increased Plasma and Endothelial Cell Expression of Chemokines and Adhesion Molecules in Chronic Kidney Disease

Chemokines and adhesion molecules are involved in early events of atherogenesis. In the present study, we investigated the effects of the uremic milieu on the expression of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) and their relationship to cardiovascular status. Plasma samples were obtained from patients in different stages of chronic kidney disease (CKD). Cardiovascular status was evaluated by intima-media thickness and endothelial dysfunction by flow mediation dilatation and proteinuria. In vitro studies were performed using human umbilical endothelial cells exposed to uremic plasma or plasma from healthy subjects. MCP-1, IL-8, sVCAM-1 and sICAM-1 levels in plasma and in supernatant were analyzed by enzyme-linked immunosorbent assay. The population consisted of 73 (mean age 57 years; 48% males) CKD patients with glomerular filtration rate (GFR) of 37 ± 2 ml/min. MCP-1 and sVCAM-1 plasma levels were negatively correlated with GFR (ρ = –0.40, p < 0.0005 and ρ = –0.42, p < 0.0005, respectively). Fibrinogen was positively correlated with MCP-1, sICAM-1 and sVCAM-1 (ρ = 0.33, p < 0.005, ρ = 0.32, p < 0.05 and ρ = 0.25, p < 0.05, respectively) and ultra-high-sensitivity C-reactive protein was positively correlated with sICAM-1 (ρ = 0.25, p < 0.0005). Plasma IL-8 had a significant positive correlation with proteinuria (ρ = 0.31, p < 0.01). There was a time- and CKD-stage-dependent MCP-1, IL-8 and sVCAM-1 endothelial expression (p < 0.05). In summary, plasma levels of markers of endothelial cell activation (MCP-1 and sVCAM-1) are increased in more advanced CKD. Exposure of endothelial cells to uremic plasma results in a time- and CKD-stage-dependent increased expression of MCP-1, IL-8 and sVCAM-1, suggesting a link between vascular activation, systemic inflammation and uremic toxicity. Future studies are necessary to investigate whether these biomarkers add predictive value in comparison to the previously described ones. Also, endothelial response to uremic toxicity should be viewed as a potential target for intervention in order to reduce morbidity and mortality in CKD-related cardiovascular disease.

Adiponectin Deficiency Promotes the Production of Inflammatory Mediators While Severely Exacerbating Hepatic Injury in Mice with Polymicrobial Sepsis

Adiponectin (APN), which is an adipose tissue-derived hormone, is known as an anti-inflammatory cytokine. The effects of APN on the production of inflammatory mediators and hepatic injury during polymicrobial sepsis were evaluated using APN-knockout (KO) mice that had undergone a cecal ligation and puncture (CLP) and rosiglitazone, a selective peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, which increases the plasma APN concentration. Wild type (WT) and APN-KO mice were underwent CLP. The plasma and hepatic levels of inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), were measured before, at 24, and 48 h after CLP. A histological analysis of the liver and the plasma alanine aminotransferase (ALT) levels were examined to evaluate hepatic injury. The plasma levels of inflammatory mediators after CLP with pretreatment of rosiglitazone were compared with those without rosiglitazone. APN deficiency resulted in significant increases in the plasma levels of TNF-alpha, IL-6, and MCP-1 at 24 h after CLP. Hepatic MCP-1 and plasma AST levels in APN-KO mice were significantly higher than those in WT mice at 48 h after CLP. A steatosis change and MCP-1 expressions in hepatocytes were induced in APN-KO mice during sepsis. The administration of rosiglitazone significantly lowered the plasma levels of inflammatory mediators, including TNF-alpha, IL-6, and MCP-1, in WT mice but not in APN-KO mice during sepsis. These results suggest that an APN deficiency induces an excessive systemic inflammatory status and exacerbates hepatic injury during polymicrobial sepsis.

JNK- and IκB-dependent pathways regulate MCP-1 but not adiponectin release from artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate in vitro

Obese conditions increase the expression of adipocytokine monocyte chemoattractant protein-1 (MCP-1) in adipose tissue as well as MCP-1 plasma levels. To investigate the mechanism behind increased MCP-1, we used a model in which 3T3-L1 adipocytes were artificially hypertrophied by preloading with palmitate in vitro. As observed in obesity, under our model conditions, palmitate-preloaded cells showed significantly increased oxidative stress and increased MCP-1 expression relative to control cells. This increased MCP-1 expression was enhanced by adding exogenous tumor necrosis factor-alpha (TNF-alpha; 17.8-fold vs. control cells, P < 0.01) rather than interleukin-1beta (IL-1beta; 2.6-fold vs. control cells, P < 0.01). However, endogenous TNF-alpha and IL-1beta release was not affected in hypertrophied cells, suggesting that these endogenous cytokines do not mediate hypertrophy-induced increase in MCP-1. MCP-1 secretion from hypertrophied cells was significantly decreased by treatment with antioxidant N-acetyl-cysteine, JNK inhibitors SP600125 and JIP-1 peptide, and IkappaB phosphorylation inhibitors BAY 11-7085 and BMS-345541 (P < 0.01). MCP-1 secretion was not affected by peroxisome proliferator-activated receptor-gamma (PPARgamma) antagonists assayed. Adiponectin, another adipocytokine studied in parallel, also showed increased release in hypertrophy relative to control cells. But in contrast to MCP-1, adiponectin release was significantly suppressed by both exogenous TNF-alpha and IL-1beta as well as by PPARgamma antagonists bisphenol A diglycidyl ether and T0070907 (P < 0.01). JNK inhibitors and IkappaB phosphorylation inhibitors showed no significant effect on adiponectin. We conclude that adipocyte hypertrophy through palmitate loading causes oxidative stress, which in turn increases MCP-1 expression and secretion through JNK and IkappaB signaling. In contrast, the parallel increase in adiponectin expression appears to be related to the PPARgamma ligand properties of palmitate.