Monocyte Chemoattractant Protein-1 Promoter Research Articles

Interleukin-6 trans-signaling regulates monocyte chemoattractant protein-1 production in immune-mediated necrotizing myopathy.

Immune-mediated necrotizing myopathy (IMNM) is pathologically characterized by diffuse myofiber necrosis and regeneration, myophagocytosis, and a sparse inflammatory infiltrate. The monocyte chemoattractant protein-1 (MCP-1) is a key chemokine that regulates monocyte/macrophage infiltration into injured tissues. The interleukin-6 (IL-6) signalling in the induction of MCP-1 expression has not been investigated in IMNM. MCP-1 expression in muscle specimens was assessed using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). Levels of multiple serological cytokines were evaluated using the Meso Scale Discovery electrochemiluminescence system. Flow cytometry, RT-qPCR, enzyme-linked immunosorbent assay, western blot, dual-luciferase reporter assays, and chromatin immunoprecipitation-qPCR were performed to explore the effects of IL-6 signalling on MCP-1 production in human myoblasts. MCP-1 was scattered and was positively expressed within myofibers and a few inflammatory cells in the muscles of patients with IMNM. Sarcoplasmic MCP-1 expression significantly correlated with myonecrosis, myoregeneration, and inflammatory infiltration. Serum MCP-1, IL-6, and the soluble form of the IL-6 receptor (sIL-6R) were elevated in patients with IMNM compared with controls. Serological MCP-1 levels were significantly associated with serum IL-6 expression and clinical disease severity in IMNM patients. The IL-6/sIL-6R complex induced MCP-1 expression via the signal transducer and activator of transcription 3 (STAT3) pathway in human myoblasts. Mechanistically, phospho-STAT3 was enriched in the MCP-1 promoter region and promoted the transcription. IL-6 trans-signalling may contribute to the immunopathogenesis of IMNM by augmenting inflammation through regulation of MCP-1 expression in IMNM.

Bioluminescence imaging of mouse monocyte chemoattractant protein-1 expression in inflammatory processes.

Monocyte chemoattractant protein-1 (MCP-1) plays a crucial role in various inflammatory diseases. To reveal the impact of MCP-1 during diseases and to develop anti-inflammatory agents, we establish a transgenic mouse line. The firefly luciferase gene is incorporated into the mouse genome and driven by the endogenous MCP-1 promoter. A bioluminescence photographing system is applied to monitor luciferase levels in live mice during inflammation, including lipopolysaccharide-induced sepsis, concanavalin A-induced T cell-dependent liver injury, CCl 4-induced acute hepatitis, and liver fibrosis. The results demonstrate that the luciferase signal induced in inflammatory processes is correlated with endogenous MCP-1 expression in mice. Furthermore, the expressions of MCP-1 and the luciferase gene are dramatically inhibited by administration of the anti-inflammatory drug dexamethasone in a septicemia model. Our results suggest that the transgenic MCP-1-Luc mouse is a useful model to study MCP-1 expression in inflammation and disease and to evaluate the efficiency of anti-inflammatory drugs in vivo.

Regulatory Factor X1 Downregulation Contributes to Monocyte Chemoattractant Protein-1 Overexpression in CD14+ Monocytes via Epigenetic Mechanisms in Coronary Heart Disease.

Monocyte chemoattractant protein 1 (MCP1) affects the chemotaxis of monocytes and is a key chemokine closely related to the development of atherosclerosis (AS). Compared with healthy controls, coronary heart disease (CAD) patients show significantly upregulated plasma concentrations and mRNA expression of MCP1 in CD14+ monocytes. However, the specific regulatory mechanism of MCP1 overexpression in AS is still unclear. Our previous research indicated that there was no significant difference in the H3K4 and H3K27 tri-methylation of the MCP1 promoter in CD14+ monocytes from CAD versus non-CAD patients, but the H3 and H4 acetylation of the MCP1 promoter was increased in CD14+ monocytes from CAD patients. We further found that the H3K9 tri-methylation of the MCP1 promoter in CD14+ monocytes from CAD patients was decreased, but the DNA methylation levels did not differ markedly from those in non-CAD patients. Our previous work showed that the level of regulatory factor X1 (RFX1) was markedly reduced in CD14+ monocytes from CAD patients and played an important role in the progression of AS by regulating epigenetic modification. In this study, we investigated whether RFX1 and epigenetic modifications mediated by RFX1 contribute to the overexpression of MCP1 in activated monocytes in CAD patients. We found that the enrichment of RFX1, histone deacetylase 1 (HDAC1), and suppressor of variegation 3–9 homolog 1 (SUV39H1) in the MCP1 gene promoter region were decreased in CD14+ monocytes from CAD patients and in healthy CD14+ monocytes treated with low-density lipoprotein (LDL). Chromatin immunoprecipitation (ChIP) assays identified MCP1 as a target gene of RFX1. Overexpression of RFX1 increased the recruitments of HDAC1 and SUV39H1 and inhibited the expression of MCP1 in CD14+ monocytes. In contrast, knockdown of RFX1 in CD14+ monocytes reduced the recruitments of HDAC1 and SUV39H1 in the MCP1 promoter region, thereby facilitating H3 and H4 acetylation and H3K9 tri-methylation in this region. In conclusion, our results indicated that RFX1 expression deficiency in CD14+ monocytes from CAD patients contributed to MCP1 overexpression via a deficiency of recruitments of HDAC1 and SUV39H1 in the MCP1 promoter, which highlighted the vital role of RFX1 in the pathogenesis of CAD.

956 Epidermal autophagy deficiency impairs skin wound healing through inhibiting keratinocyte proliferation and migration and fibroblast activation

Macroautophagy (hereafter autophagy) is a cellular catabolic process that is implicated in many physiological and pathological processes. However, the role of autophagy in skin wound healing is unknown. Here we show that epidermal autophagy deficiency impairs wound healing in mice. Epidermis-specific deletion of the autophagy essential genes Atg5 or Atg7 inhibited wound healing in mice. Epidermal autophagy deficiency inhibited wound closure, re-epithelialization, dermal granulation tissue formation, and inflammatory immune cell infiltration. Using cytokine array screening, we identified that autophagy deficiency inhibits the transcription and production of the cytokine MCP-1 (monocyte chemoattractant protein-1) viaTNF-a(tumor necrosis factor-alpha), a cytokine generated at the early stage of wound response. Furthermore, TNF-ainduced autophagy in epidermal keratinocytes. At the molecular level, TNF-a-induced autophagy promoted MCP-1 transcription through the ERK/AP-1 pathway at the AP-1 binding site of the MCP-1 promoter in keratinocytes. Furthermore, we found that autophagy promotes ERK phosphorylation through regulating the AMPK/BRAF phosphorylation signaling axis. Treatment with recombinant MCP-1 increased wound repair, reversing the wound healing phenotype in mice with epidermal autophagy deficiency. At the cellular level, we found that autophagy-mediated MCP-1 induction in keratinocytes is required not only for keratinocyte migration, but also for dermal fibroblast activation. Our findings demonstrate a critical role of epidermal autophagy in wound healing, and elucidated new molecular machineries coordinating the keratinocyte-fibroblast interaction, and may provide new opportunities by targeting the autophagy pathways to improve wound repair in affected individuals with defects in wound healing.

The effects of acarbose on chemokine and cytokine production in human monocytic THP-1 cells.

Chronic inflammation induced by proinflammatory cytokines and chemokines is postulated to be involved in insulin resistance and β-cell dysfunction in type 2 diabetes mellitus (T2DM). Acarbose, the α-glucosidase inhibitor, is an oral antidiabetic drug for T2DM. Acarbose suppresses inflammatory cytokine production in patients with T2DM, though the underlying mechanisms are unclear. In the present study, we aimed to investigate the anti-inflammatory effects and the exact mechanisms of acarbose in human monocytic THP-1 cells. THP-1 cells were pretreated with acarbose and then stimulated with lipopolysaccharide (LPS). The levels of Th1-related chemokines, including interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), Th2-related chemokine macrophage-derived chemokine (MDC), and proinflammatory cytokine tumor necrosis factor-α (TNF-α), were determined by enzyme-linked immunosorbent assay. Intracellular signaling pathways were explored by Western blot analysis and using a chromatin immunoprecipitation assay. Acarbose suppressed the levels of IP-10, MCP-1, MDC, and TNF-α and downregulated phosphorylation of p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B-p65 (NF-κB-p65) in LPS-stimulated THP-1 cells. Acarbose suppressed LPS-induced acetylation of histones H3 (H3) and H4 in the IP-10 and MCP-1 promoter regions. These findings revealed the suppressive effects of acarbose on IP-10, MCP-1, MDC, and TNF-α production in THP-1 cells via, at least partially, the p38, JNK, ERK, and NF-κB-p65 pathways, as well as through epigenetic regulation via histone H3 and H4 acetylation. Our study points to the therapeutic anti-inflammatory potential of acarbose.

MCP-1/CCL2 Mediated by Autocrine Loop of PDGF-BB Promotes Invasion of Lung Cancer Cell by Recruitment of Macrophages Via CCL2–CCR2 Axis

Platelet-derived growth factor-BB (PDGF-BB) is recognized as a potential player in a paracrine manner in tumor stroma development. PDGF-BB has an autocrine growth function in lung cancer cells; however, the mechanism in nonsmall-cell lung cancer is not fully understood. In this study, we report that PDGF-BB increased monocyte chemoattractant protein-1 (MCP-1)-dependent macrophage recruitment and that expression of metastatic genes increased in A549 cells cocultured with RAW 264.7 macrophages. Similar to exogenous PDGF-BB, PDGF-BB might have a self-stimulation in invasion of cancer cells during reciprocal activation of cancer cells and tumor-associated macrophages through secretion of soluble proteins. Also, we found that PDGF-BB upregulates both mRNA and protein level of MCP-1 expression in human A549 cells through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt cell signaling pathways, binding NFκB to MCP-1 promoter site and PDGF-Rβ as critical receptor. These results suggested that MCP-1/chemokine (C-C motif) ligand 2 (CCL2) expression mediated by the autocrine loop of PDGF-BB enhanced recruitment of macrophages through CCL2-CCR2 axis, which could ultimately increase expression of metastatic genes in lung cancer cells, finally promoting invasive potential of cancer cells.

Association of MCP-1 promoter polymorphism with susceptibility to nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is prevalent among populations from southern China and is influenced by both genetic and environmental risk factors. The monocyte chemoattractant protein-1 (MCP-1), a member of cysteine-cysteine chemokine family, plays critical roles in cancers. A polymorphism within the MCP-1 promoter, rs1024611, has been shown to be significantly associated with the risk of several cancers. Our purpose was to assess the role of rs1024611 in NPC susceptibility. By polymerase chain reaction-restriction fragment length polymorphism method, we genotyped rs1024611 in 593 patients with NPC (cases) and 480 cancer-free subjects (controls) among Guangxi population from southern China. We observed that the G allele of rs1024611 was significantly associated with the increased risk of NPC in an additive model and dominant model, respectively (P = 0.018 and 0.010, odds ratio = 1.25 and 1.41, respectively). No appreciable variation of the effects was found across the subgroups stratified by age, sex, nationality, smoking and drinking status, and smoking level. In addition, significantly higher messenger RNA (mRNA) expression level of MCP-1 was observed in NPC tissues than that in normal nasopharyngeal tissues, and the G allele of rs1024611 was significantly associated with elevated mRNA expression level of MCP-1 in Epstein-Barr virus-transformed lymphocytes. In conclusion, our findings suggested that rs1024611 at the MCP-1 promoter may be a risk factor for NPC. Further studies with larger sample size are necessary to confirm these findings.

Aberrant histone modifications of global histone and MCP-1 promoter in CD14+ monocytes from patients with coronary artery disease.

To investigate whether there are aberrant acetylation modifications in global histone and monocyte chemoattractant protein-1 (MCP-1) promoter in monocytes from patients with coronary artery disease (CAD) and demonstrate the potential mechanisms. CD14+ monocytes were isolated from 13 patients with CAD and 18 confirmed non-CAD controls using magnetic beads. Global histone H3/H4 acetylation and H3K4/H3K27 tri-methylation levels were measured with enzyme-linked immunosorbent assay. Quantitative real time-PCR was performed to detect the mRNA expression levels of MCP-1 and enzymes involved in histone modification processes. Histone modification levels in MCP-1 promoter were assessed by ChIP-qPCR assay. Our results showed a markedly lower global histone H3 acetylation level in monocytes from CAD patients. Global H3K27 tri-methylation level was significantly increased in monocytes from CAD patients. Furthermore, the mRNA expression levels of epigenetic modification enzymes HDAC3, SIRT1, P300, JMJD3 and SUV39H1 were decreased significantly in monocytes from CAD patients, while HDAC7 mRNA expression level was markedly increased. MCP-1 mRNA expression level was increased histone H3/H4 acetylation levels in MCP-1 promoter were markedly increased in monocytes of CAD patients. Aberrant histone modifications, including acetylation and tri-methylation, were found both in global histone and specific MCP-1 gene locos in monocytes from patients with CAD. Aberrant epigenetic modification enzymes expressions may be the regulatory mechanism responsible for aberrant histone modifications.

Effect of rich resistant starch snack on MCP- 1 promoter methylation and triglycerides levels in type 2 diabetes mellitus patients

Type 2 diabetes mellitus (T2DM) is closely related to inflammation. One of inflammation marker in T2DM is monocyte chemoattractant protein-1 (MCP-1). Previous research suggests that MCP-1 promoter methylation correlated significantly with plasma triglycerides levels (TG) in T2DM. Some studies state that TG levels in T2DM can be controlled through consumption of diets containing resistant starch. This study aimed to investigate the effect of high resistant starch snack on MCP-1 promoter methylation and triglycerides levels in type 2 diabetes mellitus. This study was a cross-over trial. A total of 19 T2DM subjects have been selected with the criteria of fasting blood glucose levels (GDP)>126 mg/dL, aged 40-60 years, and duration of DM at least 1 year. Subject consume snack as much as 32 g/day with the resistant starch content are 4.25 g for 4 weeks. Data collection and blood retrieval was doing before and after the intervention. The analysis of MCP-1 promoter methylation was performed by methylated specific-PCR (MS-PCR) using DNA samples extracted from mononuclear cells, whereas TG levels analysis performed by the enzymatic colorimetric method (DiaSys Kit) using blood plasma. Statistic analysis was performed by Fisher Exact test for methylation data, paired t-test and unpaired t test for TG levels, and Spearman correlation test for the correlation between variabels (p 0.05). Plasma triglyceride levels after intervention decreased, but not significant statistically. The correlation between MCP-1 promoter methylation and plasma triglyceride levels was significant. This study concludes that the giving of rich resistant starch snacks intervention does not affect MCP-1 promoter methylation changes significantly. This intervention can lead to decrease plasma triglyceride levels subjects, but not statistically significant.

Association study of MCP-1 promoter polymorphisms with the susceptibility and progression of sepsis.

Previous studies have indicated that the monocyte chemo-attractant protein 1 (MCP-1), also referred to as C-C motif chemokine ligand 2 (CCL2), plays a significant role in the pathogenesis of sepsis, and this study investigated the clinical relevance of two MCP-1 gene polymorphisms on sepsis onset and progression. The Multiplex SNaPshot genotyping method was used to detect MCP-1 gene polymorphisms in the Chinese Han population (403 sepsis patients and 400 controls). MCP-1 mRNA expression levels were measured using real-time quantitative PCR, and enzyme-linked immunosorbent assays were used to analyze MCP-1, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and interleukin-1 beta (IL-1β) plasma concentrations. The rs1024611 polymorphism analysis showed lower frequencies of minor homozygous genotype (AA) and allele (A) in sepsis patients compared to the healthy controls (19.4% vs. 31.5%, P = 0.0001 and 45.9% vs. 54.8%, P = 0.0004, respectively). And the frequencies of GG genotype and G allele were lower in sepsis patients compared to the controls (19.6% vs. 31.3%, P = 0.0002 and 46.0% vs. 54.5%, P = 0.0007, respectively). The rs1024611 AG/GG and rs2857656 GC/CC genotypes were both overrepresented in patients with severe sepsis (both P = 0.0005) and septic shock (P = 0.010 and P = 0.015, respectively) compared to the patients with mild sepsis. Moreover, among sepsis patients, the rs1024611 AG/GG and rs2857656 GC/CC carriers exhibited significant increases in expression levels of MCP-1 (P = 0.025), TNF-α (P = 0.034) and IL-6 (P = 0.043) compared with the rs1024611 AA or rs2857656 GG carriers. This study provides valuable clinical evidence that the MCP-1/CCL2 polymorphisms rs1024611 and rs2857656 are associated with sepsis susceptibility and development. We conclude that MCP-1/CCL2 plays a significant role in the pathogenesis of sepsis, which has potentially important therapeutic implications.

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.

Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation

Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatory macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue.

Activation of farnesoid X receptor downregulates monocyte chemoattractant protein-1 in murine macrophage

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, which plays important roles in bile acids/lipid homeostasis and inflammation. Monocyte chemoattractant protein-1 (MCP-1) contributes to macrophage infiltration into body tissues during inflammation. Here we investigated whether FXR can regulate MCP-1 expression in murine macrophage. FXR activation down regulate MCP-1 mRNA and protein levels in ANA-1 and Raw264.7 cells. Luciferase reporter assay, Gel shift and Chromatin immunoprecipitation assays have revealed that the activated FXR bind to the FXR element located in −738 bp ∼ −723 bp in MCP-1 promoter. These results suggested that FXR may serve as a novel target for regulating MCP-1 levels for the inflammation related diseases therapies.

Involvement of P2Y12 receptor in vascular smooth muscle inflammatory changes via MCP-1 upregulation and monocyte adhesion.

Antiplatelet drugs, frequently used for cardiovascular events with thrombotic involvement, are also regarded as possible promising agents for cardiovascular primary prevention. The roles of P2Y12, an ADP receptor and the target of thienopyridine antiplatelet drugs, are not satisfactorily known in the vascular wall. We investigated the hypothesis that vascular smooth muscle cell (VSMC) P2Y12 is involved in vascular wall inflammatory changes by upregulating monocyte chemoattractant protein-1 (MCP-1) and promoting monocyte adhesion. ADP at 10(-5) M induced a 3.6 ± 0.3-fold upregulation of MCP-1 mRNA in cultured rat VSMCs, which was significantly inhibited by R-138727, the active metabolite of P2Y12 inhibitor prasugrel and siRNAs against P2Y12. ADP also induced MCP-1 protein upregulation, which was diminished by R-138727 and P2Y12 siRNAs. JNK (c-Jun NH2-terminal kinase) inhibition attenuated ADP-induced MCP-1 mRNA and protein upregulation. R-138727 and P2Y12 siRNAs inhibited ADP-induced JNK activation. The reactive oxygen species (ROS) inhibitors N-acetylcysteine (NAC), diphenyleneiodonium (DPI), and Tempol also diminished MCP-1 upregulation and JNK activation induced by ADP. ADP induced MCP-1 promoter activation, which was inhibited by R-138727 and P2Y12 siRNAs. Nuclear factor-κB (NF-κB) consensus sites in the MCP-1 promoter region were involved in this activation. ADP-induced NF-κB pathway activation, examined by a plasmid containing multiple NF-κB sites, was diminished by P2Y12 inhibition. For cellular function analysis, stimulation of VSMC with ADP increased subsequent THP-1 monocyte adhesion. P2Y12 siRNAs and CCR2 antagonism diminished this ADP-induced monocyte adhesion. These data suggested that ADP, via the VSMC P2Y12 receptor, induces vascular inflammatory changes by upregulating MCP-1 and promoting monocyte adhesion.

A MCP-1 promoter polymorphism at G-2518A is associated with spontaneous preterm birth.

Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine involved in the pathogenesis of spontaneous preterm birth (SPTB). We examined whether the MCP-1 G-2518A polymorphism is associated with the risk of SPTB in a Chinese population. The MCP-1 G-2518A polymorphism was genotyped in 569 preterm singleton neonates and in 673 term neonates using polymerase chain reaction-restriction fragment length polymorphism analysis. The distribution of the MCP-1 G-2518A genotype and the allele frequencies between the SPTB patients and the controls were not significantly different in the overall sample. However, we found that the AA genotype was associated with significantly increased susceptibility to very SPTB (<32weeks) [odds ratio (OR) 2.07; 95% confidence interval (CI), 1.27-3.36; P=0.005) and extremely SPTB (<28weeks) (OR 2.74; 95% CI, 1.10-6.72; P=0.014) compared with -2518G-positive genotypes (GG+GA genotypes). When extremely preterm neonates and very preterm neonates were combined, the AA genotype was also significantly associated with increased susceptibility to SPTB (OR 2.23; 95% CI, 1.40-3.54; P<0.001). The MCP-1 G-2518A polymorphism was not associated with increased susceptibility to SPTB in patients with premature rupture of the membranes (PROM) or in those without PROM. Our findings suggest that the MCP-1 G-2518A polymorphism may plays a role in mediating the susceptibility to SPTB in the Chinese population. Knowledge of genetic factors contributing to the pathogenesis of SPTB may have implications for screening and treatment of this disorder.

Relationship between MCP-1 promoter -2518 A/G gene polymorphism (rs1024611) and systemic lupus erythematosus/lupus nephritis

Results from the published studies on the association between monocyte chemoattractant protein-1 (MCP-1) promoter -2518 A/G (rs1024611) gene polymorphism and systemic lupus erythematosus (SLE)/lupus nephritis (LN) are still conflicting. This meta-analysis was performed to evaluate the relationship between MCP-1 A/G gene polymorphism and SLE/LN and to explore whether MCP-1 A allele, AA genotype or GG genotype could become a predictive marker for SLE/LN risk. Association studies were identified from the databases of PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) as of 1 January 2014, and eligible investigations were synthesized using meta-analysis method. Results were expressed with odds ratios (OR) for dichotomous data, and 95% confidence intervals (CI) were also calculated. Sixteen investigations were identified for the analysis of association between MCP-1 A/G gene polymorphism and SLE, consisting of 2425 patients with SLE and 2567 controls. In the overall populations, Asians, Caucasian population, the association between MCP-1 A/G gene polymorphism and SLE susceptibility was not found. Interestingly, a trend toward an association between A allele/AA genotype and LN risk was observed in overall populations, although there was no statistical difference. However, this meta-analysis indicated that AA genotype was associated with LN risk in Caucasians (OR = 0.71; 95% CI: 0.54–0.93; p = 0.01). In conclusion, our results indicate that AA homozygous might be a significant genetic molecular marker to predict the SLE patients developing into LN in Caucasians. However, more investigations are required to further clarify this association.

Hydrogen Sulfide Suppresses Oxidized Low-density Lipoprotein (Ox-LDL)-stimulated Monocyte Chemoattractant Protein 1 generation from Macrophages via the Nuclear Factor κB (NF-κB) Pathway

This study was designed to examine the role of hydrogen sulfide (H2S) in the generation of oxidized low-density lipoprotein (ox-LDL)-stimulated monocyte chemoattractant protein 1 (MCP-1) from macrophages and possible mechanisms. THP-1 cells and RAW macrophages were pretreated with sodium hydrosulfide (NaHS) and hexyl acrylate and then treated with ox-LDL. The results showed that ox-LDL treatment down-regulated the H2S/cystathionine-β-synthase pathway, with increased MCP-1 protein and mRNA expression in both THP-1 cells and RAW macrophages. Hexyl acrylate promoted ox-LDL-induced inflammation, whereas the H2S donor NaHS inhibited it. NaHS markedly suppressed NF-κB p65 phosphorylation, nuclear translocation, DNA binding activity, and recruitment to the MCP-1 promoter in ox-LDL-treated macrophages. Furthermore, NaHS decreased the ratio of free thiol groups in p65, whereas the thiol reductant DTT reversed the inhibiting effect of H2S on the p65 DNA binding activity. Most importantly, site-specific mutation of cysteine 38 to serine in p65 abolished the effect of H2S on the sulfhydration of NF-κB and ox-LDL-induced NF-κB activation. These results suggested that endogenous H2S inhibited ox-LDL-induced macrophage inflammation by suppressing NF-κB p65 phosphorylation, nuclear translocation, DNA binding activity, and recruitment to the MCP-1 promoter. The sulfhydration of free thiol group on cysteine 38 in p65 served as a molecular mechanism by which H2S inhibited NF-κB pathway activation in ox-LDL-induced macrophage inflammation.

Thicker Carotid Intima Media Thickness in Children with Monocyte Chemoattractant Protein-1: A-2138T and A-2464G Mutation.

Carotid intima media thickness (CIMT) is clearly associated with atherosclerosis. Studies in ischemic stroke patients reveal that there is a significant association between CIMT with monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN) promoter polymorphism. This research aims to explain the effect of MCP-1 and OPN promoter polymorphism toward CIMT changes identified in Javanese Indonesian children. Subjects were 54 children: 27 were from parents with ischemic stroke (cases), and 27 were from healthy parents (controlled). The CIMT was examined by utilizing high resolution B-mode ultrasound. Physical examination and genotyping analysis of MCP-1 promoter were conducted by employing PCR method. Research results indicate that two polymorphisms were obtained, that is, A-2138T and G-2464A, respectively. A-2138T polymorphism was found in 5% of case children and in 14.3% of controlled children. G-2464A polymorphism was found in 5% of case children. CIMT of case children was significantly different from that of controlled children (0.61 ± 0.012 mm versus, 0.52 ± 0.015 mm, P = 0.021). Subjects with MCP-1 promoter polymorphism have 1.471 times higher tendency to have thicker CIMT than subjects with no polymorphism in MCP1 promoter. OPN promoter T-66G was also studied but it did not indicate occurrence of polymorphism in samples.

MCP-1 in psoriatic patients: effect of biological therapy

Background: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine locally and systemically augmented in psoriasis. A single nucleotide polymorphism in MCP-1 promoter region -2518A→G is associated with higher gene expression. Objective: The aim was to evaluate MCP-1 plasma level in psoriatic patients and to relate any association in plasmatic and cutaneous MCP-1 with clinical improvement due to biological drugs. Methods: Blood samples were obtained from: (i) 30 Caucasian patients with psoriasis and 10 controls, for determining MCP-1 plasma concentrations and -2518A→G polymorphism occurrence, (ii) 16 psoriatic patients treated by anti-tumor necrosis factor-α (TNF-α) adalimumab/etanercept or by anti-CD-11 efalizumab, before and after 2 months of treatment. Moreover, biopsies were performed on lesional skin of five patients treated with anti-TNF-α. MCP-1 plasma concentration and cutaneous expression were determined by ELISA and qRT-PCR. Results: MCP-1 plasma level was significantly increased in psoriatic patients. -2518A→G polymorphism was similarly distributed in patients and controls and unrelated to MCP-1 plasma level or to Psoriasis Area and Severity Index. All patients receiving biological drugs showed significant clinical improvement. Anti-TNF-α therapy moderately reduced MCP-1 plasma concentration and robustly decremented MCP-1 expression in lesional skin. Conclusion: MCP-1 should be a potential local inflammatory marker in psoriatic patients to assess disease severity and anti-TNF-α treatment efficacy.

Hyperhomocysteinemia-Induced Monocyte Chemoattractant Protein-1 Promoter DNA Methylation by Nuclear Factor-κB/DNA Methyltransferase 1 in Apolipoprotein E–Deficient Mice

Hyperhomocysteinemia is considered to be a significant risk factor in atherosclerosis and plays an important role in it. The purpose of this study was to determine the molecular mechanism of blood monocyte chemoattractant protein-1 (MCP-1) promoter DNA hypomethylation in the formation of atherosclerosis induced by hyperhomocysteinemia, and to explore the effect of nuclear factor-κB (NF-κB)/DNA methyltransferase 1 (DNMT1) in this mechanism. The atherosclerotic effect of MCP-1 in apolipoprotein E–deficient (ApoE−/−) and wild-type C57BL/6J mice was evaluated using atherosclerotic lesion area; serum NF-κB, MCP-1, and DNMT1 levels; and MCP-1 promoter DNA methylation expression. In vitro, the mechanism responsible for the effect of NF-κB/DNMT1 on foam cells was investigated by measuring NF-κB and DNMT1 levels to determine whether NF-κB/DNMT1 had an effect on gene expression. Compared with the control group, atherosclerotic lesions in ApoE−/− mice fed a high methionine diet significantly increased, as did the expression of MCP-1. In vitro study showed that pyrrolidine dithiocarbamate treatment down-regulated levels of NF-κB and raised DNMT1 concentrations, confirming the effect of NF-κB/DNMT1 in the MCP-1 promoter DNA methylation process. In conclusion, our results suggest that through NF-κB/DNMT1, MCP-1 promoter DNA hypomethylation may play a key role in formation of atherosclerosis under hyperhomocysteinemia.