Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P80098 (monocyte chemoattractant protein)
 1,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Respiratory virus infection evokes a potent T-cell response that may result in a considerable insult to the structural and functional integrity of the gas exchange units of the lung. Alveolar antigen recognition by CD8+ T lymphocytes results in significant injury that is critically dependent upon tumor necrosis factor (TNF)-alpha expressed by the CD8+ T cells and is largely dependent upon TNF-receptor 1 expression on the alveolar epithelial target cells. TNF-receptor 2 (TNF-R2)-deficient mice were used to demonstrate that CD8+ T-cell-mediated lung injury associated with clearance of experimental influenza requires TNF-R2 for full expression of immunopathology. In vitro analysis indicates that alveolar cell expression of TNF-R2 is critical in the induction of epithelial monocyte chemoattractant protein (MCP)-1 expression specifically in response to soluble TNF-alpha, suggesting an important role for this receptor in bystander lung injury. However, TNF-R2 was dispensable for induction of alveolar MCP-1 expression in response to transmembrane TNF-alpha expressed by antigen-specific CD8+ T cells, and the effects of the two receptors seem to be additive. Because TNF-R2 may be rapidly shed as part of feedback inhibition of bystander inflammation, this suggests a mechanism by which immunopathology in respiratory virus infection may be regulated and by which T-cell receptor-dependent TNF-alpha activity might bypass such negative regulation for contact-dependent antiviral activities.
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PMID:Requirement for tumor necrosis factor-receptor 2 in alveolar chemokine expression depends upon the form of the ligand. 1608 83

Cerebrospinal fluid (CSF) biological markers may be of valuable help in the diagnosis of dementia. The aim of the present study was to evaluate CSF levels of 13 potential biomarkers in patients with Alzheimer's disease (AD), frontotemporal lobe dementia, alcohol dementia, major depression and control patients without any neuropsychiatric disease. The study was performed using beta-amyloid 1-42 (Abeta42), total tau and phosphorylated tau-181 (P-tau181) as core markers. The ratio P-tau181/Abeta42 could significantly distinguish AD patients from all other diagnostic subgroups. CSF levels of 5 growth factors (HGF, GDNF, VEGF, BDNF, FGF-2) and 3 cytokines/chemokines (TNF-alpha, TGF-beta1, MIP-1alpha) did not significantly differentiate between the studied groups. However, depending on the degree of neurodegeneration (as expressed by the ratio P-tau181/Abeta42), patients with AD displayed significantly increased CSF levels of nerve growth factor (NGF) as compared to healthy controls. CSF levels of monocyte chemoattractant protein 1 (MCP-1) were found to be significantly increased with age in all groups but did not distinguish AD patients from healthy controls. The results confirmed the suitability of the ratio P-tau181/Abeta42 for the diagnosis of AD, while CSF levels of NGF and MCP-1 are less specific and reliable for AD. It is suggested that the increase in NGF depends on the extent of neurodegeneration of the AD type and the increase in MCP-1 on age.
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PMID:Measurement of thirteen biological markers in CSF of patients with Alzheimer's disease and other dementias. 1624 82

Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis and inflammation. Inhibition of activation and cell functions of PSCs is a potential target for the treatment of pancreatic fibrosis and inflammation. The polyphenol compound curcumin is the yellow pigment in curry, and has anti-inflammatory and anti-fibrotic properties. We here evaluated the effects of curcumin on the activation and cell functions of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. The effects of curcumin on proliferation, alpha-smooth muscle actin gene expression, monocyte chemoattractant protein (MCP)-1 production, and collagen expression were examined. The effect of curcumin on the activation of freshly isolated cells in culture was also assessed. Curcumin inhibited platelet-derived growth factor (PDGF)-induced proliferation, alpha-smooth muscle actin gene expression, interleukin-1beta- and tumor necrosis factor (TNF)-alpha-induced MCP-1 production, type I collagen production, and expression of type I and type III collagen genes. Curcumin inhibited PDGF-BB-induced cyclin D1 expression and activation of extracellular signal-regulated kinase (ERK). Curcumin inhibited interleukin-1beta- and TNF-alpha-induced activation of activator protein-1 (AP-1) and mitogen-activated protein (MAP) kinases (ERK, c-Jun N-terminal kinase (JNK), and p38 MAP kinase), but not of nuclear factor-kappaB (NF-kappaB). In addition, curcumin inhibited transformation of freshly isolated cells to myofibroblast-like phenotype. In conclusion, curcumin inhibited key cell functions and activation of PSCs.
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PMID:Curcumin blocks activation of pancreatic stellate cells. 1629 27

The antioxidant response element (ARE) is a transcriptional control element that mediates expression of a set of antioxidant proteins. NF-E2-related factor 2 (Nrf2) is a transcription factor that activates ARE-containing genes. In endothelial cells, the ARE-mediated genes are upregulated by atheroprotective laminar flow through a Nrf2-dependent mechanism. We tested the hypothesis that activation of ARE-regulated genes via adenovirus-mediated expression of Nrf2 may suppress redox-sensitive inflammatory gene expression. Expression of Nrf2 in human aortic endothelial cells (HAECs) resulted in a marked increase in ARE-driven transcriptional activity and protected HAECs from H2O2-mediated cytotoxicity. Nrf2 suppressed TNF-alpha-induced monocyte chemoattractant protein (MCP)-1 and VCAM-1 mRNA and protein expression in a dose-dependent manner and inhibited TNF-alpha-induced monocytic U937 cell adhesion to HAECs. Nrf2 also inhibited IL-1beta-induced MCP-1 gene expression in human mesangial cells. Expression of Nrf2 inhibited TNF-alpha-induced activation of p38 MAP kinase. Furthermore, expression of a constitutively active form of MKK6 (an upstream kinase for p38 MAP kinase) partially reversed Nrf2-mediated inhibition of VCAM-1 expression, suggesting that p38 MAP kinase, at least in part, mediates Nrf2's anti-inflammatory action. In contrast, Nrf2 did not inhibit TNF-alpha-induced NF-kappaB activation. These data identify the Nrf2/ARE pathway as an endogenous atheroprotective system for antioxidant protection and suppression of redox-sensitive inflammatory genes, suggesting that targeting the Nrf2/ARE pathway may represent a novel therapeutic approach for the treatment of inflammatory diseases such as atherosclerosis.
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PMID:Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. 1633 37

Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) and liver X receptor alpha (LXRalpha) play pivotal roles in macrophage cholesterol homeostasis and inflammation, key biological processes in atherogenesis. Herein we identify adipocyte enhancer-binding protein 1 (AEBP1) as a transcriptional repressor that impedes macrophage cholesterol efflux, promoting foam cell formation, via PPARgamma1 and LXRalpha down-regulation. Contrary to AEBP1 deficiency, AEBP1 overexpression in macrophages is accompanied by decreased expression of PPARgamma1, LXRalpha, and their target genes ATP-binding cassette A1, ATP-binding cassette G1, apolipoprotein E, and CD36, with concomitant elevation in IL-6, TNF-alpha, monocyte chemoattractant protein 1, and inducible NO synthase levels. AEBP1, but not the C-terminally truncated DNA-binding domain mutant (AEBP1DeltaSty), represses PPARgamma1 and LXRalpha in vitro. Expectedly, AEBP1-overexpressing transgenic (AEBP1TG) macrophages accumulate considerable amounts of lipids compared with AEBP1 nontransgenic macrophages, making them precursors for foam cells. Indeed, AEBP1-overexpressing transgenic macrophages exhibit diminished cholesterol efflux compared with AEBP1 nontransgenic macrophages, whereas AEBP1-knockout (AEBP1-/-) macrophages exhibit enhanced cholesterol efflux compared with wild-type (AEBP1+/+) macrophages. Our in vitro and ex vivo experimental data strongly suggest that AEBP1 plays critical regulatory roles in macrophage cholesterol homeostasis, foam cell formation, and proinflammation. Thereby, we speculate that AEBP1 may be critically implicated in the development of atherosclerosis, and it may serve as a molecular target toward developing antiinflammatory, antiatherogenic therapeutic approaches.
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PMID:Adipocyte enhancer-binding protein 1 is a potential novel atherogenic factor involved in macrophage cholesterol homeostasis and inflammation. 1646 8

Interindividual differences of endothelial cells in response to endotoxins might contribute to the diversity in clinical outcome among septic patients. The present study was conducted to test the hypothesis that endothelial cells (EC) with high and low proinflammatory potential exist and to dissect the molecular basis underlying this phenomenon. Thirty human umbilical vein endothelial cell (HUVEC) lines were stimulated for 24 h with lipopolysaccharide (LPS) and screened for interleukin (IL)-8 production. Based on IL-8 production five low and five high producers, tentatively called types I and II responders, respectively, were selected for genome-wide gene expression profiling. From the 74 genes that were modulated by LPS in all type II responders, 33 genes were not influenced in type I responders. Among the 41 genes that were increased in both responders, 17 were expressed significantly stronger in type II responders. Apart from IL-8, significant differences in the expression of proinflammatory related genes between types I and II responders were found for adhesion molecules [intercellular adhesion molecule (ICAM-1), E-selectin)], chemokines [monocyte chemoattractant protein (MCP-1), granulocyte chemotactic protein (GCP-2)], cytokines (IL-6) and the transcription factor CCAAT/enhancer binding protein-delta (C/EBP-delta). Type I responders also displayed a low response towards tumour necrosis factor (TNF)-alpha. In general, maximal activation of nuclear factor (NF)-kappaB was achieved in type I responders at higher concentrations of LPS compared to type II responders. In the present study we demonstrate that LPS-mediated gene expression differs quantitatively and qualitatively in types I and II responders. Our results suggest a pivotal role for common transcription factors as a low inflammatory response was also observed after TNF-alpha stimulation. Further studies are required to elucidate the relevance of these findings in terms of clinical outcome in septic patients.
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PMID:Heterogeneity in lipopolysaccharide responsiveness of endothelial cells identified by gene expression profiling: role of transcription factors. 1648 52

Seminal fluid is known to be responsible for orchestrating mating-induced immunomodulation. Central to this process are numerous cytokines that modulate uterine leukocyte recruitment and trafficking. Despite this, a comprehensive analysis of the cytokine profile of murine seminal fluid is lacking. This study addressed this issue by using multiplex immunoassays to characterise the profile of interleukin (IL)-1alpha , IL-1beta , IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17, eotaxin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon (IFN)-gamma, keratinocyte-derived chemokine (KC), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha , MIP-1beta , regulated upon activation normal T-cell expressed and secreted (RANTES), and tumour necrosis factor (TNF)-alpha in fluid drawn from the seminal vesicles of single mice (n = 18). Their levels and ratios were compared with those found in serum. IL-1alpha , IL-1beta , IL-2, IL-5, IL-9, IL-12 (p40), IL-12 (p70), IL-13, IL-17, GM-CSF, IFN-gamma, MCP-1 and TNF-alpha levels were significantly higher in serum; IL-4, G-CSF, eotaxin, KC and RANTES exhibited the opposite trend. Based on these findings, we propose a model of mating-induced immunomodulation that implicates seminal eotaxin, RANTES and MIP-1alpha in the relocation and concentration of extravasated migrating endometrial eosinophils to the luminal epithelium. Furthermore, KC may participate in uterine neutrophil chemotaxis and activation. Eotaxin and MIP-alpha , together with IL-1beta and IL-9, may also enhance further cytokine synthesis for endometrial antigen-presenting cell recruitment for processing paternal ejaculate antigens. IL-4 and G-CSF could also minimise deleterious cell-mediated immunity and modulate IFN-gamma production, thereby supporting the establishment of pregnancy.
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PMID:Multiplex determination of murine seminal fluid cytokine profiles. 1651 4

Proteinuria (albuminuria) reflects dysfunction of the glomerular permeability barrier in which inflammatory cytokines play a key role. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses potent anti-inflammatory and immunomudulatory effects. This study evaluated the effectiveness of PTX to reduce proteinuria and inflammatory mediators in patients with proteinuric primary glomerular diseases. Seventeen patients with primary glomerular diseases, a persistent spot proteinuria exceeding 1.5 g/g creatinine (Cr) and a glomerular filtration rate between 24 and 115 ml/min/1.73 m(2) were treated with PTX 400 mg twice daily for 6 months. Before and after the treatment, serum Cr, plasma renin activity and aldosterone concentrations, plasma and urinary tumor necrosis factor (TNF)-alpha, interleukin-1beta and monocyte chemoattractant protein (MCP)-1, as well as urinary protein and Cr were measured. PTX significantly reduced urinary protein excretion, along with an increase of serum albumin. A significant correlation existed between the basal urinary protein/Cr and the basal urinary MCP-1/Cr ratios. PTX lowered the urinary MCP-1/Cr ratio, and the percent reduction of urinary protein/Cr ratio correlated directly with the precent decrease of urinary MCP-1/Cr ratio after PTX treatment. There was no significant change in blood pressure, renal function, biochemical parameters, plasma renin activity and aldosterone concentrations, or plasma TNF-alpha and MCP-1 levels during the study. In conclusion, administration of PTX 800 mg per day is safe and effective for reducing proteinuria in patients with proteinuric primary glomerular diseases. This beneficial effect occurs in close association with a reduction of urinary MCP-1 excretion.
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PMID:Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. 1654 Oct 21

Human parvovirus B19 (B19) has been associated with a variety of autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We have demonstrated previously that B19 non-structural protein (NS1) induced apoptosis through the mitochondria cell death pathway in COS-7 epithelial cells and that B19 NS1 may play a role in the pathogenesis of autoimmune diseases. In order to examine the expression profiles of cytokines and chemokines in B19 NS1 transfected COS-7 cells, we constructed the NS1 gene in the pEGFP-C1 vector named enhanced green fluorescence protein gene (EGFP)-NS1. COS-7 cells were transfected with EGFP or EGFP-NS1 plasmid. The expression profiles of cytokines and chemokines, including interleukin (IL)-1beta, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-related oncogene alpha (GROalpha), interferon gamma-inducible protein (IP)-10, stromal cell derived factor (SDF)-1, macrophage inflammatory protein (MIP)-1beta, monocyte chemoattractant protein (MCP)-1, regulated upon activation normal T cell expressed and secreted (RANTES), Fractalkine, CX3CR1, CCR2, CCR5 and CCR11 were examined in COS-7 cells, EGFP and EGFP-NS1 transfected cells using enzyme-linked immunosorbent assay (ELISA) or reverse transcription-polymerase chain reaction (RT-PCR). Increased expression and levels of IL-6 were found in EGFP-NS1 transfected cells using RT-PCR and ELISA. There were no significant increases in the expression of IL-1beta, IL-8, IP-10, SDF-1, RANTES, Fractalkine, CX3CR-1, CCR2, CCR5, CCR11, TNF-alpha, GM-CSF and TGF-beta using RT-PCR. There were no significantly increased levels of IL-5, IL-10, TNF-alpha, TGF-beta, GROalpha, MIP-1beta and MCP-1 found by ELISA in this study. Our results show that increased expression and secretion of IL-6 in B19 NS1 transfected epithelial cells may play a role in the pathogenesis of autoimmune diseases.
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PMID:Increased expression and secretion of interleukin-6 in human parvovirus B19 non-structural protein (NS1) transfected COS-7 epithelial cells. 1654 77

Quercetin (3,3',4',5,7-pentahydroxyflavone), a dietary flavonoid, is an inhibitor of phosphatidylinositol (PI) 3-kinase and potent antioxidant. We hypothesized that quercetin blocks airway epithelial cell chemokine expression via PI 3-kinase-dependent mechanisms. Pretreatment with quercetin and the PI 3-kinase inhibitor LY294002 each reduced TNF-alpha-induced IL-8 and monocyte chemoattractant protein (MCP)-1 (also called CCL2) expression in cultured human airway epithelial cells. Quercetin also inhibited TNF-alpha-induced PI 3-kinase activity, Akt phosphorylation, intracellular H(2)O(2) production, NF-kappaB transactivation, IL-8 promoter activity, and steady-state mRNA levels, consistent with the notion that quercetin inhibits chemokine expression by attenuating NF-kappaB transactivation via a PI 3-kinase/Akt-dependent pathway. Quercetin also reduced TNF-alpha-induced chemokine secretion in the presence of the transcriptional inhibitor actinomycin D, while inducing phosphorylation of eukaryotic translation initiation factor (eIF)-2alpha, suggesting that quercetin attenuates chemokine expression by post-transcriptional as well as transcriptional mechanisms. Finally, we tested the effects of quercetin in cockroach antigen-sensitized and -challenged mice. These mice show MCP-1-dependent airways hyperresponsiveness and inflammation. Quercetin significantly reduced lung MCP-1 and methacholine responsiveness. We conclude that quercetin blocks airway cell chemokine expression via transcriptional and post-transcriptional pathways.
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PMID:Quercetin blocks airway epithelial cell chemokine expression. 1679 57


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