Circulating Monocyte Chemoattractant Protein-1 Research Articles

Circulating Monocyte Chemoattractant Protein-1 (MCP-1) in Patients with Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease that leads to the destruction of the intrahepatic bile ducts. While the inflammatory process can be mediated by monocyte chemotactic protein-1 (MCP-1), the importance of circulating MCP-1 as a biomarker is unclear. Our aim was to assess the diagnostic significance of the serum concentrations of MCP-1 in PBC patients. We compared circulating MCP-1 with biochemical, immunological and histological parameters. Serum samples were collected from 120 PBC patients, 60 pathologic controls and 30 healthy donors. MCP-1 levels were determined by using commercial enzyme-linked immunosorbent assay (ELISA). Elevated serum MCP-1 levels were detected in 66% of PBC patients with a specificity of 97%. Significantly higher levels of MCP-1 protein were found in the sera of patients with PBC than in the group of healthy individuals-410.2 pg/mL vs. 176.0 pg/mL, p < 0.01). Patients with higher concentrations of alkaline phosphatase also had higher levels of MCP-1 (r = 0.4, p < 0.01). In accordance with Ludwig's classification, a positive correlation of serum MCP-1 concentration with the degree of fibrosis was observed, OR = 6.1, p = 0.0003. We compared the MCP-1 with procollagen type III, hyaluronic acid (HA), FIB-4 index, APRI and collagen type IV when predicting the advance of liver fibrosis. Circulating MCP-1 is better correlated with liver fibrosis and is also associated with the occurrence of specific antimitochondrial autoantibodies and specific anti-nuclear autoantibodies-anti-gp210. MPC-1 can be considered to be a tool for diagnosing the degree of fibrosis in PBC, and combinations of MCP-1 and other specific biomarkers could support the diagnosis of PBC.

Circulating Monocyte Chemoattractant Protein-1 in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction Treated with Mild Hypothermia: A Biomarker Substudy of SHOCK-COOL Trial

Background: There is evidence that monocyte chemoattractant protein-1 (MCP-1) levels reflect the intensity of the inflammatory response in patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI) and have a predictive value for clinical outcomes. However, little is known about the effect of mild therapeutic hypothermia (MTH) on the inflammatory response in patients with CS complicating AMI. Therefore, we conducted a biomarker study to investigate the effect of MTH on MCP-1 levels in patients with CS complicating AMI. Methods: In the randomized mild hypothermia in cardiogenic shock (SHOCK-COOL) trial, 40 patients with CS complicating AMI were enrolled and assigned to MTH (33 °C) for 24 h or normothermia at a 1:1 ratio. Blood samples were collected at predefined time points at the day of admission/day 1, day 2 and day 3. Differences in MCP-1 levels between and within the MTH and normothermia groups were assessed. Additionally, the association of MCP-1 levels with the risk of all-cause mortality at 30 days was analyzed. Missing data were accounted for by multiple imputation as sensitivity analyses. Results: There were differences in MCP-1 levels over time between patients in MTH and normothermia groups (P for interaction = 0.013). MCP-1 levels on day 3 were higher than on day 1 in the MTH group (day 1 vs day 3: 21.2 [interquartile range, 0.25–79.9] vs. 125.7 [interquartile range, 87.3–165.4] pg/mL; p = 0.006) and higher than in the normothermia group at day 3 (MTH 125.7 [interquartile range, 87.3–165.4] vs. normothermia 12.3 [interquartile range, 0–63.9] pg/mL; p = 0.011). Irrespective of therapy, patients with higher levels of MCP-1 at hospitalization tended to have a decreased risk of all-cause mortality at 30 days (HR, 2.61; 95% CI 0.997–6.83; p = 0.051). Conclusions: The cooling phase of MTH had no significant effect on MCP-1 levels in patients with CS complicating AMI compared to normothermic control, whereas MCP-1 levels significantly increased after rewarming. Trial registration: NCT01890317.

High-fat diet increases the level of circulating Monocyte Chemoattractant Protein-1 in Wistar rats, independent of obesity

IntroductionLow-grade chronic inflammation has emerged as a key pathogenic link between high-fat diet (HFD)–induced obesity and the increased risk of chronic diseases. Evidence has shown that HFDs may induce inflammation in the central nervous system and peripheral tissues. Monocyte Chemoattractant Protein-1 (MCP-1) is a product of various cells that is known to be an inflammatory marker. This study investigated whether a HFD could induce obesity and increase the level of MCP-1 in Wistar rats. MethodsThe Wistar rats were randomized into two groups: normal diet (ND) and HFD (n = 12 per group). Both groups were fed for 8 and 16 weeks, thus dividing the rats into 4 arms: ND8, ND16, HFD8, and HFD16 (n = 6 per sub-group). Obesity in rats was measured using the Lee index. Blood samples were taken to measure the level of MCP-1. ResultsOur results showed that obesity did not occur in the group with a normal diet (ND8 and ND16). However, in the HFD group (HFD8 and HFD16), 4 of the 6 rats became obese. However, MCP-1 was significantly higher among non-obese rats in the HFD group compared with the ND group (p < 0.001). ConclusionHFDs have been shown to increase the risk of obesity. In addition, increases in circulating MCP-1 were significantly different between Wistar rats given a HFD compared with the ND group.

Association of circulating monocyte chemoattractant protein-1 levels with polycystic ovary syndrome: A meta-analysis.

Polycystic ovary syndrome (PCOS) is a common hormonal disorder that has a huge impact on the human infertility. Increased levels of various circulating inflammatory cytokines have been observed in PCOS patients, which can contribute to the pathogenesis of PCOS. Monocyte chemoattractant protein-1 (MCP-1), a secretory chemokine, is a potent chemotactic factor that recruits monocytes/macrophages to inflammatory foci. Several previous studies comparing the circulating MCP-1 levels between non-PCOS and PCOS patients have yielded contradictory results. Therefore, the aim of this meta-analysis was to investigate whether circulating MCP-1 levels vary between non-PCOS and PCOS patients. Research articles published before November 11, 2020, were screened to identify eligible studies. Heterogeneity, sensitivity, and publication bias were analyzed using STATA software. Standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated by the STATA software using a random-effects model. 11 studies were included in this meta-analysis involving 897 individuals: 368 non-PCOS patient and 529 PCOS patients. Our pooled meta-analysis results show that circulating MCP-1 levels were significantly higher in PCOS patients than in non-PCOS patients (SMD=0.84, 95% CI=[0.37, 1.31], Z=3.50, p<0.01). However, due to the limited number of studies included in this meta-analysis, subgroup analysis determined that circulating MCP-1 levels were not significantly varied between obese non-PCOS and obese PCOS patients (SMD=0.42, 95% CI=[-0.65, 1.49], Z=0.77, p=0.442) as well as between non-PCOS and PCOS patients without obesity (SMD=2.04, 95% CI=[-0.84, 4.93], Z=1.39, p=0.166). In addition, circulating MCP-1 levels were also not significantly different between obese and non-obese PCOS patients (SMD=-0.04, 95% CI=[-0.68, 0.60], Z=0.11, p=0.909). Our findings reveal that circulating MCP-1 levels are upregulated in women with PCOS and are associated with an increased risk of PCOS.

Correction to: Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals.

Correction to: Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals.

Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors.

BackgroundBromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors.MethodsThis was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker.ResultsSixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60–100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%–42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3–7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months.ConclusionsOnce-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.

Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals.

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

Circulating Mcp-1 Associated With Prolonged Cycling In Hot Temperature

PURPOSE: The purpose of this investigation was to examine the recruitment of classical monocytes during prolonged aerobic exercise in high temperature and humidity conditions. METHODS: Seven recreationally active men (23.4 ± 3.0 yrs; 180.9 ± 5.8 cm; 85.1 ± 11.3 kg; 3.7 ± 0.27 L∙min-1) completed five trials: a graded exercise test, and four cycling trials in 37°C/23% Relative Humidity (RH)(HTLH), 37°C/33%RH (HTMH), 24°C/38%RH (MTMH), and 24°C/51%RH (MTHH) in a counterbalanced fashion. During the exercise protocol, participants rested supine for 15 minutes before completing 60-min of cycling at 60% VO2max, a 15-min rest, and cycling until exhaustion at 90% VO2max (TTE), before 60 minutes of recovery. Blood samples were obtained prior to exercise (PRE), after 60 minutes of cycling (60), after the TTE (90) and following one hour of recovery (REC). Blood was assessed for plasma concentrations of Monocyte Chemoattractant Protein 1 (MCP-1) via ELISA, and CCR2 expression on classical monocytes (CD14++CD16-) via flow cytometry. Briefly, CCR2 expression was determined as fold change over fluorescence minus one (FMO). Data were analyzed using within-subjects repeated measures ANOVA. RESULTS: A main effect for time was observed (F = 8.9; p = 0.003; η2p = 0.560) for MCP-1 in circulation. MCP-1 increased from PRE (183.8 ± 59.7 pg.mL-1) to 60 (215.8 ± 74.1 pg.mL-1; p = 0.009), 90 (231.6 ± 83.8 pg.mL-1; p = 0.006), and REC (216.0 ± 88.3 pg.mL-1; p = 0.019). Concentrations also increased from 60 to 90 (p = 0.018). A main effect of time was also observed (F = 11.6; p = 0.009; η2p = 0.659) for CCR2 expression on classical monocytes. No differences in CCR2 expression were observed between PRE (147.4 ± 50.6), and 60 (146.0 ± 70.8; p = 0.869), however decreases from PRE were observed at 90 (131.1 ± 39.7; p = 0.023), and REC (102.2 ±37.1; p < 0.001). CONCLUSION: These data indicate that high temperature and/or humidity conditions do not impact recruitment of classical monocytes. Furthermore, prolonged cycling appears to increase circulating MCP-1 and decrease CCR2 expression on classical monocytes. Collectively, this may indicate a limited effect of aerobic exercise on the overall recruitment of classical monocytes, although further research is warranted. This investigation was partially funded by the Kent State University Research Council.

Delayed activation of PPAR-β/δ improves long-term survival in mouse sepsis: effects on organ inflammation and coagulation.

Activation of peroxisome proliferator-activated receptor (PPAR)-β/δ reduces tissue injury in murine endotoxemia. We hypothesized that the PPAR-β/δ-agonist GW0742 improves long-term outcome after sepsis caused by cecal ligation and puncture (CLP). Fifty-one CD-1 female mice underwent CLP and received either vehicle (control), GW0742 (0.03 mg/kg/injection; five post-CLP i.v. injections), GSK0660 (PPAR-β/δ-antagonist) or both and were monitored for 28 d. Another 20 CLP mice treated with GW0742 and vehicle were sacrificed 24 h post-CLP to assess coagulopathy. Compared to vehicle, survival of CLP-mice treated with GW0742 was higher by 35% at d 7 and by 50% at d 28. CLP mice treated with GW0742 had 60% higher IFN-γ but circulating monocyte chemoattractant protein-1 and chemokine ligand were lower at 48 h post-CLP. Compared to vehicle, CLP mice treated with GW0742 exhibited a 50% reduction in the circulating plasminogen activator inhibitor-1 associated with an increase in platelet number at 24 h post-CLP (but no changes occurred in anti-thrombin-III, plasminogen, fibrinogen and clotting-times). CLP mice treated with GW0742 exhibited a similar increase in most of the biochemical markers of organ injury/dysfunction (lactate dehydrogenase, alanine aminotransferase, creatine kinase, creatinine, blood urea nitrogen, and triglycerides) measured. Treatment with GW0742 consistently improved long-term survival in septic CD-1 mice by partially modulating the post-CLP systemic cytokine response and coagulation systems.

Circulating Monocyte Chemoattractant Protein-1 Levels and Lumbar Bone Mineral Density in Korean Women.

BackgroundMonocyte chemoattractant protein-1 (MCP-1) is expressed in adipose tissue, macrophages, endothelial cells, and osteoblasts by parathyroid hormone administration. Circulating MCP-1 levels are positively correlated with the degree of obesity. However, whether circulating MCP-1 affects bone metabolism is unclear. Therefore, in this study, the association between circulating MCP-1 levels and lumbar bone mineral density (BMD) based on menopausal status was assessed.MethodsWe recruited 109 premenopausal and 46 postmenopausal Korean women and examined the association between circulating MCP-1 concentrations and various parameters including lumbar BMD based on menopausal status.ResultsA significant increase in body weight, abdominal circumference, body mass index, and MCP-1 levels (from 245.9±73.5 to 336.5±101.7 pg/mL) and significant decrease (from 0.992±0.114 to 0.772±0.113 g/cm2) in lumbar BMD were observed after menopause. However, circulating MCP-1 levels were not correlated with any parameters including lumbar BMD in premenopausal or postmenopausal women.ConclusionCirculating MCP-1 levels were not correlated with lumbar BMD regardless of menopausal status.

Monocyte chemoattractant protein-1 polymorphism interaction with spirulina immunomodulatory effects in healthy Korean elderly: A 16 week, double-blind randomized clinical trial.

BACKGROUND/OBJECTIVESSpirulina is a known a functional food related to lipid profiles, immune functions, and antioxidant capacity. Circulating monocyte chemoattractant protein-1 (MCP-1) level is associated with inflammation markers. Single nucleotide polymorphism in the MCP-1 promoter region -2518 have been identified and shown to affect gene transcription. Gene variation may also impact functional food supplementary effects. The current study investigated the interaction of MCP-1 -2518 polymorphism with spirulina supplements on anti-inflammatory capacity in Korean elderly.SUBJECTS/METHODSAfter genotyping, healthy elderly subjects (n = 78) were included in a randomized, double blind, and placebo controlled study. Baseline characteristic, body composition, and dietary intake were measured twice (baseline vs. week 16). For 16 weeks, subjects consumed 8 g either spirulina or placebo daily. Plasma MCP-1, interleukin (IL) -2, IL-6, tumor necrosis factor (TNF)-α, complement (C) 3, immunoglobulin (Ig) G, and Ig A concentrations and lymphocyte proliferation rate (LPR) were analyzed as inflammatory markers.RESULTSIn the placebo group with A/A genotype, MCP-1 level was significantly increased, but the spirulina group with A/A genotype was unchanged. IL-2 was significantly increased only in subjects with spirulina supplementation. TNF-α was significantly reduced in subjects with the G carrier. C3 was significantly increased in the placebo group, particularly when A/A increased more than G, but not when spirulina was ingested. LPR was significantly different only in subjects with A/A genotype; there was a significant increase in phytohemagglutinin and lipopolysaccharide induced LPR in the spirulina group.CONCLUSIONIn healthy Korean elderly, spirulina supplementation may influence different inflammatory markers by the MCP-1 genotype. These results may be useful for customized dietary guidelines to improve immune function in Koreans.

Monocyte Chemoattractant Protein-1 Levels and Postangioplasty Restenosis of Arteriovenous Fistulas.

Inflammation is relevant in restenosis of atherosclerotic vascular diseases, but its role in dialysis arteriovenous fistula remains unknown. In animal studies, upregulation of monocyte chemoattractant protein-1 has been shown in venous segments of arteriovenous fistula. We, therefore, aimed to investigate serial changes in circulating monocyte chemoattractant protein-1 after percutaneous transluminal angioplasty of dialysis arteriovenous fistulas and its relation to restenosis. Fifty-nine patients with dysfunctional arteriovenous fistulas that were referred for percutaneous transluminal angioplasty were enrolled prospectively between January of 2010 and July of 2012. Three of them were excluded due to percutaneous transluminal angioplasty failure or acute infection. Blood was sampled from arteriovenous fistulas at baseline, 2 days, 2 weeks, and 3 months after percutaneous transluminal angioplasty. Clinical follow-up was continued monthly for 3 months. Angiographic follow-up was arranged at the end of 3 months. Seventeen patients without significant stenosis were enrolled as the control group. Fifty-six patients completed clinical follow-up. Significant increases in monocyte chemoattractant protein-1 were observed at 2 days and 2 weeks (both P<0.001) after percutaneous transluminal angioplasty. Twenty-three (41%) patients had symptomatic restenosis. The restenosis group had a higher percentage change in monocyte chemoattractant protein-1 levels at 2 days (median =47%; interquartile range, 27%-65% versus median =17%; interquartile range, 10%-25%; P<0.001) after percutaneous transluminal angioplasty compared with the patent group. Fifty-two patients completed angiographic follow-up. A positive correlation between relative luminal loss and monocyte chemoattractant protein-1 increase at 2 days after percutaneous transluminal angioplasty was found (r=0.53; P<0.001). In multivariate analysis, postangioplasty monocyte chemoattractant protein-1 increase at 2 days was an independent predictor of restenosis. Using receiver operator characteristic analysis, >25% postangioplasty increase of monocyte chemoattractant protein-1 was significantly associated with restenosis after percutaneous transluminal angioplasty (hazard ratio, 5.36; 95% confidence interval, 1.81 to 15.8). Circulating monocyte chemoattractant protein-1 levels were elevated 2 days and 2 weeks after percutaneous transluminal angioplasty. Early postangioplasty increase of monocyte chemoattractant protein-1 level was associated with restenosis of arteriovenous fistulas.

Macrophages clear refrigerator storage-damaged red blood cells and subsequently secrete cytokines in vivo, but not in vitro, in a murine model.

In mice, refrigerator-stored red blood cells (RBCs) are cleared by extravascular hemolysis and induce cytokine production. To enhance understanding of this phenomenon, we sought to model it in vitro. Ingestion of refrigerator-stored murine RBCs and subsequent cytokine production were studied using J774A.1 mouse macrophage cells and primary murine splenic macrophages. Wild-type and Ccl2-GFP reporter mice were used for RBC clearance in vivo. Although J774A.1 cells and primary macrophages preferentially ingested refrigerator-stored RBCs in vitro, compared to freshly isolated RBCs, neither produced increased cytokines after erythrophagocytosis. In contrast, phagocytosis of refrigerator-stored RBCs in vivo induced increases in circulating monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC) and correspondingly increased mRNA levels in mouse spleen and liver. In the spleen, these were predominantly expressed by CD11b+ cells. Using Ccl2-GFP reporter mice, the predominant splenic population responsible for MCP-1 mRNA production was tissue-resident macrophages (i.e., CD45+, CD11b+, F4/80+, Ly6c+, and CD11c(low) cells). J774A.1 cells and primary macrophages selectively ingested refrigerator-stored RBCs by phagocytosis. Although cytokine expression was not enhanced, this approach could be used to identify the relevant receptor-ligand combination(s). In contrast, cytokine levels increased after phagocytosis of refrigerator-stored RBCs in vivo. These were primarily cleared in the liver and spleen, which demonstrated increased MCP-1 and KC mRNA expression. Finally, in mouse spleen, tissue-resident macrophages were predominantly involved in MCP-1 mRNA production. The differences between cytokine production in vitro and in vivo are not yet well understood.

Effect of Folic Acid Supplementation on Levels of Circulating Monocyte Chemoattractant Protein-1 and the Presence of Intravascular Ultrasound Derived Virtual Histology Thin-Cap Fibroatheromas in Patients with Stable Angina Pectoris

BackgroundVirtual Histology Intravascular Ultrasound (VH–IVUS) may be used to detect early signs of unstable coronary artery disease. Monocyte Chemoattractant Protein-1 (MCP-1) is linked with coronary atherosclerosis and plaque instability and could potentially be modified by folic acid treatment.MethodsIn a randomized, prospective study, 102 patients with stable angina pectoris (SAP) received percutaneous coronary intervention and established medical treatment as well as either homocysteine-lowering folic acid/vitamin B12 (±B6) or placebo (±B6) for 1 year before VH–IVUS was performed. The presence of VH-Thin-Cap Fibroatheroma (VH-TCFA) in non-intervened coronary vessels was registered and serum levels of MCP-1 were measured. The patients were subsequently followed for incident myocardial infarction (MI).ResultsPatients treated with folic acid/vitamin B12 had a geometric mean (SD) MCP-1 level of 79.95 (1.49) versus 86.00 (1.43) pg/mL for patients receiving placebo (p-value 0.34). VH-TCFA lesions were present in 7.8% of patients and did not differ between intervention arms (p-value 0.47). Serum levels of MCP-1 were 1.46 (95% CI 1.12 to 1.92) times higher in patients with VH-TCFA lesions than in those without (p-value 0.005). Afterwards, patients were followed for median 2.1 years and 3.8% experienced a myocardial infarction (MI), which in post-hoc Cox regression analyses was independently predicted by both MCP-1 (P-value 0.006) and VH-TCFA (p-value 0.01).ConclusionsIn patients with SAP receiving established medical treatment, folic acid supplementation is not associated with either presence of VH-TCFA or levels of MCP-1. MCP-1 is however associated with VH-TCFA, a finding corroborated by increased risk for future MI. ClinicalTrials.gov Identifier: NCT00354081.

11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis.

11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11β-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11β-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11β-HSD1 inhibitor or crossed with 11β-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11β-HSD1 inhibition or deficiency attenuated atherosclerosis (74–76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11β-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11β-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11β-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.—Kipari, T., Hadoke, P. W. F., Iqbal, J., Man, T. Y., Miller, E., Coutinho, A. E., Zhang, Z., Sullivan, K. M., Mitic, T., Livingstone, D. E. W., Schrecker, C., Samuel, K., White, C. I., Bouhlel, M. A., Chinetti-Gbaguidi, G., Staels, B., Andrew, R., Walker, B. R., Savill, J. S., Chapman, K. E., Seckl, J. R. 11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis.

Sex Steroid-Induced Changes in Circulating Monocyte Chemoattractant Protein-1 Levels May Contribute to Metabolic Dysfunction in Obese Men

Low testosterone accompanied by elevated estradiol associates with the development of metabolic dysfunction in men. The aim of the study was to explore the hypothesis that alterations in sex steroid levels induce metabolic dysfunction through adipokines. Circulating levels of sex steroids and 28 adipokines were determined in a cross-sectional study of morbidly obese men and aged-matched controls, as well as in a randomized clinical trial with healthy young men in which obesity-related alterations in sex steroid levels were mimicked by treatment with an aromatase inhibitor plus estradiol patches. Morbidly obese men had lower testosterone levels than normal-weight controls. Estradiol levels were increased in morbidly obese men (without DM2) as compared to normal-weight controls. Circulating levels of multiple proinflammatory cytokines, including IL-1Ra, IL-5, IL-6, IL-10, leptin, monocyte chemoattractant protein 1 (MCP1), and macrophage inflammatory protein 1α, positively associated with estradiol and negatively with testosterone. The associations with estradiol, but not with testosterone, remained significant after adjusting for adipocyte cell size. In a separate clinical trial, the direct adverse effects of lowering testosterone and raising estradiol on MCP1 were substantiated in vivo. Initial alterations in sex steroid levels may contribute to metabolic dysfunction through adverse effects on adipokine levels in obese men. The direct adverse effects on MCP1, a chemokine highly linked to the development of metabolic dysfunction, were substantiated in a trial mimicking obesity-related alterations of sex steroid levels in healthy young males.

Induction of circulating monocyte chemoattractant protein-1 in women with gonadotropin-releasing hormone agonist

The aim of the present study was to determine the influence of acute estrogen deficiency induced by administration of a gonadotropin-releasing hormone (GnRH) agonist on circulating levels of cytokines and chemokines. Eighty-three women with uterine leiomyoma were assigned in open, parallel-group fashion to a no-treatment (control) group and a GnRH-agonist group. Serum levels of nine cytokines and chemokines as well as vascular inflammatory markers were measured. Serum levels of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor-α (TNFα) in the GnRH-agonist group were increased significantly at 6 months. There were also significant differences in percentage changes in interleukin (IL)-6, IL8, MCP1, and macrophage inflammatory protein-1β (MIP1β) between the control and GnRH agonist groups. Soluble intercellular adhesion molecule-1 (sICAM1) and E-selectin levels showed significant increases in the GnRH agonist group at 6 months. Serum MCP1 concentrations showed weak correlations with levels of sICAM and E-selectin. We conclude that a hypo-estrogenic state due to administration of a GnRH agonist increases circulating levels of cytokines and chemokines, especially MCP1.

Circulating monocyte chemoattractant protein-1 links to diabetic retinopathy in type 2 diabetic patients without renal dysfunction

Monocyte chemoattractant protein-1 (MCP-1) is a cytokine thought to be an important factor in adipose tissue inflammation in obese patients, but little is known about circulating MCP-1 in type 2 diabetic patients. We studied circulating MCP-1 levels in type 2 diabetic patients and their correlation with insulin resistance and other clinical data including chronic complications. In a preliminary study of 114 non-diabetic subjects, we found a significant correlation between serum MCP-1 level and estimated glomerular filtration rate (eGFR). We thus enrolled 185 type 2 diabetic patients and 91 non-diabetic subjects with an eGFR more than 60 ml/min/1.73 m2. There was no difference in serum MCP-1 levels between diabetic patients and non-diabetic subjects. Serum MCP-1 levels had no significant correlation with high-molecular-weight adiponectin in type 2 diabetic patients. In a limited number of type 2 diabetic patients (N = 112), serum MCP-1 levels had no significant correlation with homeostasis model assessment for insulin resistance (P = 0.075). Serum MCP-1 level was higher in proliferative retinopathy patients than in non-retinopathy patients (P = 0.028). Multiple regression analysis revealed that serum MCP-1 level was correlated with diabetic retinopathy (P = 0.007). We conclude that circulating MCP-1 level has little correlation with insulin resistance but is linked with diabetic retinopathy in type 2 diabetic patients.

An Increase in the Circulating Concentration of Monocyte Chemoattractant Protein-1 Elicits Systemic Insulin Resistance Irrespective of Adipose Tissue Inflammation in Mice

Chronic inflammation in adipose tissue is thought to be important for the development of insulin resistance in obesity. Furthermore, the level of monocyte chemoattractant protein-1 (MCP-1) is increased not only in adipose tissue but also in the circulation in association with obesity. However, it has remained unclear to what extent the increased circulating level of MCP-1 contributes to insulin resistance. We have now examined the relevance of circulating MCP-1 to the development of insulin resistance in mice. The plasma concentration of MCP-1 was increased chronically or acutely in mice to the level observed in obese animals by chronic subcutaneous infusion of recombinant MCP-1 with an osmotic pump or by acute intravenous infusion of MCP-1 with an infusion pump, respectively. Whole-body metabolic parameters as well as inflammatory changes in adipose tissue were examined. A chronic increase in the circulating level of MCP-1 induced insulin resistance, macrophage infiltration into adipose tissue, and an increase in hepatic triacylglycerol content. An acute increase in the circulating MCP-1 concentration also induced insulin resistance but not macrophage infiltration into adipose tissue. In addition, inhibition of signaling by MCP-1 and its receptor CCR2 by administration of a novel CCR2 antagonist ameliorated insulin resistance in mice fed a high-fat diet without affecting macrophage infiltration into adipose tissue. These data indicate that an increase in the concentration of MCP-1 in the circulation is sufficient to induce systemic insulin resistance irrespective of adipose tissue inflammation.

Association between circulating monocyte chemoattractant protein-1 and urinary albumin excretion in nonobese Type 2 diabetic patients

In 70 nonobese inpatients with Type 2 diabetes [body mass index (BMI): 24.0±4.4 kg/m 2], we examined circulating monocyte chemoattractant protein (MCP) -1 as a candidate marker of atherosclerosis by comparison with established markers: serum high-sensitivity C-reactive protein (hsCRP), plasma fibrinogen, and combined carotid artery intimal–medial thickness (IMT). In addition, an association was sought between circulating MCP-1 and urinary albumin excretion (UAE), reflecting diabetic renal microangiopathy. Serum MCP-1 was determined by enzyme-linked immunosorbent assay (ELISA). Patients were grouped by UAE: normoalbuminuria, below 30 mg/g of creatinine (Cr); microalbuminuria, 30 to 300 mg/g Cr; or macroalbuminuria, over 300 mg/g Cr. Serum MCP-1 for all participants, men, and women was 280.0±78.9, 269.0±68.8, and 294.9±87.9 pg/ml, respectively, showing no difference between genders. No correlation was noted between MCP-1 and hsCRP, fibrinogen, or carotid artery IMT. No correlation of MCP-1 was observed with age, duration of diabetes, fasting plasma glucose (FPG), hemoglobin (Hb) A 1C, BMI, diastolic blood pressure (DBP), or serum lipid concentrations, but significant correlations were found with systolic blood pressure (SBP; R=.2723, P=.0225) and with log 10-transformed (log) UAE ( R=.3343, P=.0047). Patients with macroalbuminuria had significant higher circulating MCP-1 than did those with normo- or microalbuminuria ( P=.0063 and P=.0188, respectively). By stepwise regression analysis, only log UAE independently predicted serum MCP-1 ( β=.3700, P=.0020). Thus, in nonobese Type 2 diabetic patients, MCP-1 might not be a marker of atherosclerosis and might be influenced significantly by diabetic nephropathy.