Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C/EBPbeta is a member of the CCAAT/enhancer binding protein family of transcription factors and has been shown to be a critical transcriptional regulator of various proinflammatory genes, including IL-6 and MCP-1. To examine the roles of the C/EBPbeta transactivation and regulatory domains in LPS-induced MCP-1 and IL-6 expression, we expressed various N-terminal truncations and deletions of C/EBPbeta in P388 murine B lymphoblasts, which lack endogenous C/EBPbeta expression and are normally unresponsive to LPS for expression of IL-6 and MCP-1. Unexpectedly, a region between amino acids 105 and 212 of C/EBPbeta that includes regulatory domains 1 and 2 facilitates C/EBPbeta activation of IL-6 expression, while having an inhibitory effect on MCP-1 expression. Thus, this region can mediate promoter-specific effects on cytokine and chemokine gene transcription. LIP, the naturally occurring truncated form of C/EBPbeta, largely retains these regulatory domains and stimulates IL-6 but not MCP-1 transcription.
Mol Immunol 2007 Feb
PMID:Differential roles of C/EBP beta regulatory domains in specifying MCP-1 and IL-6 transcription. 1678 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.
Am J Respir Cell Mol Biol 2006 Nov
PMID:Quercetin blocks airway epithelial cell chemokine expression. 1679 57

Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and is implicated in inflammation. We investigated the effects of the PPAR-alpha activator fenofibrate on, as well as the role of redox-regulated transcription factors, in the development of left ventricular (LV) hypertrophy and heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed a high-salt diet and treated with either fenofibrate (30 or 50 mg/kg per day) or vehicle from 7 weeks of age. Fenofibrate inhibited the development of compensated hypertensive LV hypertrophy, attenuated the LV relaxation abnormality and systolic dysfunction, and improved the survival rate in DS rats. It also prevented a decrease in the ratio of reduced to oxidized glutathione and inhibited up-regulation of the DNA binding activities of the redox-regulated transcription factors NF-kappaB, AP-1, Egr-1, SP1, and Ets-1 induced in the left ventricle by the high-salt diet. Expression of target genes for these transcription factors, including those for adhesion molecules (VCAM-1, ICAM-1), cytokines (MCP-1), growth factors (TGF-beta, PDGF-B), and osteopontin, was also increased by the high-salt diet in a manner sensitive to treatment with fenofibrate. Furthermore, the infiltration of macrophages and T lymphocytes into the left ventricle and the increase in the plasma concentration of C-reactive protein were inhibited by fenofibrate. The PPAR-alpha activator fenofibrate thus attenuated the progression of heart failure and improved the survival rate in this rat model. These effects were associated with inhibition of the inflammatory response and of activation of redox-regulated transcription factors in the left ventricle.
J Mol Cell Cardiol 2006 Aug
PMID:Attenuation of cardiac dysfunction by a PPAR-alpha agonist is associated with down-regulation of redox-regulated transcription factors. 1680 63

Acute right ventricular (RV) failure following pulmonary embolism (PE) is a strong predictor of poor clinical outcome. Present studies test for an association between RV failure from experimental PE, inflammation, and upregulated chemokine expression. Additional experiments test if neutrophil influx contributes to RV dysfunction. PE was induced in male rats by infusing 24 microm microspheres (right jugular vein) producing mild hypertension (1.3 million beads/100 g, PE1.3), or moderately severe hypertension (2.0 million beads/100 g, PE2.0). Additional rats served as vehicle sham (0.01% Tween 20, Veh). In vivo RV peak systolic pressures (RVPSP) increased significantly, and then declined following PE2.0 (51 +/- 1 mm Hg 2 h; 49 +/- 1, 6 h; 44 +/- 1, 18 h). RV generated pressure of isolated, perfused hearts was significantly reduced in PE2.0 compared with PE1.3 or Veh. MCP-1 protein (ELISA) was elevated 21-fold and myeloperoxidase activity 95-fold in RV of PE2.0 compared with Veh or PE1.3. CINC-1, CINC-2, MIP-2, MCP-1, and MIP-1alpha mRNA also increased in RV of PE2.0. Histological analysis revealed massive accumulation of neutrophils (selective esterase stain) and monocyte/macrophages (CD68, ED-1) in RV of PE2.0 hearts in regions of myocyte damage. Electron microscopy showed myocyte necrosis and phagocytosis by inflammatory cells. LV function was normal and did not show increased inflammation after PE2.0. Treatment with anti-PMN antibody reduced RV MPO activity and prevented RV dysfunction. Conclusions-PE with moderately severe pulmonary hypertension (PE2.0) resulted in selective RV dysfunction, which was associated with increased chemokine expression, and infiltration of both neutrophils and monocyte/macrophages, indicating that a robust immune response occurred with RV damage following experimental PE. Experimental agranulocytosis reduced RV, suggesting that neutrophil influx contributed to RV damage.
J Mol Cell Cardiol 2006 Aug
PMID:Cardiac inflammation contributes to right ventricular dysfunction following experimental pulmonary embolism in rats. 1681 20

Lung ischemia-reperfusion (I/R) injury is a biphasic inflammatory process. Previous studies indicate that the later phase is neutrophil-dependent and that alveolar macrophages (AMs) likely contribute to the acute phase of lung I/R injury. However, the mechanism is unclear. AMs become activated and produce various cytokines and chemokines in many inflammatory responses, including transplantation. We hypothesize that AMs respond to I/R by producing key cytokines and chemokines and that depletion of AMs would reduce cytokine/chemokine expression and lung injury after I/R. To test this, using a buffer-perfused, isolated mouse lung model, we studied the impact of AM depletion by liposome-clodronate on I/R-induced lung dysfunction/injury and expression of cytokines/chemokines. I/R caused a significant increase in pulmonary artery pressure, wet-to-dry weight ratio, vascular permeability, tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-2 expression, as well as decreased pulmonary compliance, when compared with sham lungs. After AM depletion, the changes in each of these parameters between I/R and sham groups were significantly attenuated. Thus AM depletion protects the lungs from I/R-induced dysfunction and injury and significantly reduces cytokine/chemokine production. Protein expression of TNF-alpha and MCP-1 are positively correlated to I/R-induced lung injury, and AMs are a major producer/initiator of TNF-alpha, MCP-1, and MIP-2. We conclude that AMs are an essential player in the initiation of acute lung I/R injury.
Am J Physiol Lung Cell Mol Physiol 2006 Nov
PMID:Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury. 1686 85

Increasing evidence has shown advanced glycation end products (AGEs) receptor ligation (RAGE) to be an important part of complex interactions of the oxidative stress and pro-inflammatory responses. In this study, flavonoids were used to monitor the protective effects against the oxidative damage and inflammation mediated by AGEs in human monocytes. S100B (RAGE ligand) treatment in human THP-1 monocytic cells (THP-1) significantly increased gene expression of the pro-inflammatory cytokines TNF-alpha and IL-1beta; chemokines MCP-1 and IP-10; adhesion factors platelet endothelial cell adhesion molecule (PECAM-1) and beta2-integrin; and pro-inflammatory cyclooxygenase-2 (COX-2). S100B treatment with quercetin and catechin in THP-1 cells had inhibitory effects on the expression of pro-inflammatory genes and protein levels. Quercetin and catechin could regulate S100B-activated oxidant stress-sensitive pathways through blocking p47phox protein expression. Treatment with quercetin and catechin could eliminate reactive oxygen species (ROS) to reduce oxidative stress stimulated by S100B in THP-1 cells. Quercetin and catechin also showed different regulatory abilities on mitogen-activated protein kinase (MAPK) signaling pathways by inhibiting protein expression in S100B-stimulated inflammatory responses in THP-1 cells. This study suggests that quercetin and catechin may be of benefit for diabetic vascular complications due to its antioxidant abilities against AGE-mediated oxidative stress through oxidative stress-sensitive and oxidative stress-responsive signaling pathways, which lead to inflammation in human monocytes.
Mol Nutr Food Res 2006 Dec
PMID:Effects of flavonoids on the expression of the pro-inflammatory response in human monocytes induced by ligation of the receptor for AGEs. 1710 73

The aim of the current study was to elucidate the potential therapeutic effect of Ganoderma lucidum polysaccharide peptide (GL-PP) in rheumatoid arthritis (RA). The effects of GL-PP on cell proliferation and cytokine production were studied in RA synovial fibroblasts (RASF). GL-PP significantly inhibited the proliferation of RASF. Following the incubation with GL-PP, production of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 in RASF were significantly increased as expressed as percentage change from basal values. However, the actual effects were minimal due to the low basal values. When RASF were activated by IL-1beta or lipopolysaccharides, IL-8 and MCP-1 production increased many folds. GL-PP significantly suppressed their productions. The inhibitory effects of GL-PP on cytokine production in RASF were at least in part, by inhibiting the nuclear factor-kappa B (NF-kappaB) transcription pathway. Our results demonstrated that GL-PP had the unique ability to modulate cytokine production in RASF and warrants further investigation into its mechanism of action.
Mol Cell Biochem 2007 Jul
PMID:Ganoderma lucidum polysaccharide peptide reduced the production of proinflammatory cytokines in activated rheumatoid synovial fibroblast. 1721 61

The presence of immune cells is important for plaque destabilization. Disturbed flow conditions were shown to enhance the recruitment of circulating immune cells. Thus, we analyzed in 54 atherosclerotic carotid plaques the frequency of different immune cells, HLA-DR, chemokines, and chemokine receptors, comparing the upstream with the downstream plaque shoulder. The presence of neovascularization and intraplaque hemorrhages was investigated by CD34 immunostaining and Mallory's iron stain. Immunohistochemical analyses were performed to detect smooth muscle cells (SMC: actin), macrophages (CD68), T cells (CD3), dendritic cells (DC: fascin), mature DC (CD83), and the expression of HLA-DR, chemokine receptors (CCR-2, CCR-6), and chemokines (MCP-1, MIP-3alpha). Significantly more SMC were detected downstream than upstream (p<0.001). In contrast, significantly more macrophages (p=0.01), DC (p=0.03), mature DC (p=0.007), and a higher expression of HLA-DR (p=0.004), CCR-2 (p=0.002), CCR-6 (p<0.001), MCP-1 (p=0.04), and MIP-3alpha (p=NS) were observed upstream than downstream. Immune cells were strongly associated with neovascularization. The abundance of SMC downstream provides an explanation for distal plaque growth. Enhanced recruitment of immune cells through neovessels into the upstream shoulder might be contributing to plaque destabilization.
Exp Mol Pathol 2007 Jun
PMID:Accumulation of immune cells and high expression of chemokines/chemokine receptors in the upstream shoulder of atherosclerotic carotid plaques. 1722 20

Toll-like receptors (TLR) recognize not only microbial products, but also danger signals released from damaged tissues. Although we have previously shown that TLR4 is upregulated following trauma hemorrhage, the exact role of TLR4 in the posttraumatic immune response is unclear. To study this, C3H/HeOuJ (functional TLR4) or C3H/HeJ (TLR4 mutant) mice were subjected to laparotomy and hemorrhagic shock followed by resuscitation with 4x the shed blood volume in the form of Ringer's lactate. Sham operated mice underwent same surgical procedure, but neither hemorrhage nor resuscitation was performed. Four hours after resuscitation, the mice were sacrificed, plasma and lungs were collected and Kupffer cells were isolated. Plasma chemokine (MCP-1 and KC) levels, Kupffer cell chemokine production, and lung chemokine content were determined. Lung neutrophil infiltration was assessed by tissue content of myeloperoxidase. The chemokine levels in plasma, Kupffer cell supernatants and lung tissue were elevated in C3H/HeOuJ mice subjected to trauma hemorrhage compared to shams. No such changes were observed in C3H/HeJ mice undergoing trauma hemorrhage. Mice with functional TLR4 expression showed elevated lung neutrophil infiltration following trauma hemorrhage, which was not observed in TLR4 mutant mice. These findings suggest that functional TLR4 signaling is critical in mediating the inflammatory response following trauma hemorrhage. Thus, modulation of the TLR4 after injury may serve as a future therapeutic target in trauma patients.
Mol Immunol 2007 Apr
PMID:TLR4 regulates Kupffer cell chemokine production, systemic inflammation and lung neutrophil infiltration following trauma-hemorrhage. 1723 39

The mis-regulation of nuclear factor-kappa B (NF-kappaB) signal pathway is involved in a variety of inflammatory diseases that leds to the production of inflammatory mediators. Our studies using human U937 promonocytes cells suggested that magnolol, a low molecular weight lignan isolated from the medicinal plant Magnolia officinalis, differentially down-regulated the pharmacologically induced expression of NF-kappaB-regulated inflammatory gene products MMP-9, IL-8, MCP-1, MIP-1alpha, TNF-alpha. Pre-treatment of magnolol blocked TNF-alpha-induced NF-kappaB activation in different cell types as evidenced by EMSA. Magnolol did not directly affect the binding of p65/p50 heterodimer to DNA. Immunoblot analysis demonstrated that magnolol inhibited the TNF-alpha-stimulated phosphorylation and degradation of the cytosolic NF-kappaB inhibitor IkappaBalpha and the effects were dose-dependent. Mechanistically, a non-radioactive IkappaB kinases (IKK) assay using immunoprecipitated IKKs protein demonstrated that magnolol inhibited both intrinsic and TNF-alpha-stimulated IKK activity, thus suggesting a critical role of magnolol in abrogating the phosphorylation and degradation of IkappaBalpha. The involvement of IKK was further verified in a HeLa cell NF-kappaB-dependent luciferase reporter system. In this system magnolol suppressed luciferase expression stimulated by TNF-alpha and by the transient transfection and expression of NIK (NF-kappaB-inducing kinase), wild type IKKbeta, constitutively active IKKalpha and IKKbeta, or the p65 subunit. Magnolol was also found to inhibit the nuclear translocation and phosphorylation of p65 subunit of NF-kappaB. In line with the observation that NF-kappaB activation may up-regulate anti-apoptotic genes, it was shown in U937 cells that magnolol enhanced TNF-alpha-induced apoptotic cell death. Our results suggest that magnolol or its derivatives may have potential anti-inflammatory actions through IKK inactivation.
Mol Immunol 2007 Apr
PMID:Magnolol suppresses NF-kappaB activation and NF-kappaB regulated gene expression through inhibition of IkappaB kinase activation. 1724 Apr 50


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