Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid-induced TNF receptor family related protein ligand (GITRL) is known to interact with its cognate receptor GITR. In order to investigate the potential role of GITRL in the pro-inflammatory activation of macrophages and the signaling pathway induced by GITRL, we stimulated the macrophage cell line, THP-1, and primary macrophages with an anti-GITRL monoclonal antibody or a GITR:Fc fusion protein and analyzed the cellular responses. The stimulation of GITRL induced the expression of pro-inflammatory cytokines and matrix metalloproteinase (MMP)-9 and up-regulated ICAM-1 expression levels, which was responsible for enhanced cellular aggregation and adhesion to extracellular matrix proteins. The activation of these pro-inflammatory mediators required the activation of ERK1/2 mitogen-activated protein kinase (MAPK) and negatively regulated by p38 MAPK and JNK. Immunofluorescence analysis detected nuclear translocation of the NF-kappaB p50 subunit and this was blocked by ERK inhibitor, indicating that GITRL stimulation induced ERK1/2 phosphorylation and subsequent activation of NF-kappaB. Furthermore, the expression of GITRL and GITR was detected in macrophages in inflammatory disease specimens such as atherosclerotic plaques and synovial tissues of rheumatoid arthritis. These observations raise the possibility that the GITRL-mediated inflammatory activation of macrophages is involved in the pathogenesis of inflammatory diseases.
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PMID:Reverse signaling initiated from GITRL induces NF-kappaB activation through ERK in the inflammatory activation of macrophages. 1760 48

Rhinovirus (RV) infections trigger exacerbations of airways disease, but underlying mechanisms remain unknown. We hypothesized that RV and cytokines present in inflamed airways combine to induce augmented airway epithelial cell chemokine expression, promoting further inflammation. To test this hypothesis in a cellular system, we examined the combined effects of RV39 and TNF-alpha, a cytokine increased in asthma and chronic obstructive pulmonary disease, on airway epithelial cell proinflammatory gene expression. Costimulation of 16HBE14o- human bronchial epithelial cells and primary mucociliary-differentiated tracheal epithelial cells with RV and TNF-alpha induced synergistic increases in IL-8 and epithelial neutrophil attractant-78 production. Similar synergism was observed for IL-8 promoter activity, demonstrating that the effect is transcriptionally mediated. Whereas increases in ICAM-1 expression and viral load were noted 16-24 h after costimulation, cooperative effects between RV39 and TNF-alpha were evident 4 h after stimulation and maintained despite incubation with blocking antibody to ICAM-1 given 2 h postinfection or UV irradiation of virus, implying that effects were not solely due to changes in ICAM-1 expression. Furthermore, RV39 infection induced phosphorylation of ERK and transactivation of the IL-8 promoter AP-1 site, which functions as a basal level enhancer, leading to enhanced TNF-alpha responses. We conclude that RV infection and TNF-alpha stimulation induce cooperative increases in epithelial cell chemokine expression, providing a cellular mechanism for RV-induced exacerbations of airways disease.
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PMID:Cooperative effects of rhinovirus and TNF-{alpha} on airway epithelial cell chemokine expression. 1763 13

Leptin is a pleiotropic adipocyte-derived cytokine used in hypothalamic regulation of body weight and modulation of immune response by stimulating T cells, macrophages and neutrophils. Leptin has been shown to be an eosinophil survival factor. We examined the immunopathological mechanisms for the activation of human eosinophils from healthy volunteers by leptin in allergic inflammation. Adhesion molecules, cytokines and cell migration were assessed by flow cytometry, ELISA and Boyden chamber assay, respectively. Intracellular signaling molecules were investigated by membrane array and Western blot. Leptin could up-regulate cell surface expression of adhesion molecule ICAM-1 and CD18 but suppress ICAM-3 and L-selectin on eosinophils. Leptin could also stimulate the chemokinesis of eosinophils, and induce the release of inflammatory cytokines IL-1beta and IL-6, and chemokines IL-8, growth-related oncogene-alpha and MCP-1. We found that leptin-mediated induction of adhesion molecules, release of cytokines and chemokines, and chemokinesis were differentially regulated by the activation of ERK, p38 MAPK and NF-kappaB. In view of the above results and elevated production of leptin in patients with allergic diseases such as atopic asthma and atopic dermatitis, leptin could play crucial immunopathophysiological roles in allergic inflammation by activation of eosinophils via differential intracellular signaling cascades.
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PMID:Leptin-mediated cytokine release and migration of eosinophils: implications for immunopathophysiology of allergic inflammation. 1763 54

Hypothermic perfusion is a standard method for neuroprotection during cardiac surgery in children. However, the cellular responses underlying these mechanisms have not been clearly elucidated. In the present study we demonstrated that the inflammatory response of stimulated microglial cells is significantly reduced after moderate hypothermia. Continuous hypothermia caused a diminished NO release. Moderate hypothermia and rewarming caused a downregulation of phosphorylated MEK, ERK and iNOS-expression, diminished cytokine release and reduced CD-11a and ICAM-1 expression. Thus, neuroprotection offered by hypothermia could be attributed to reduced cytotoxic products released from stimulated microglial cells mediated by the MEK/ERK signal transduction pathway.
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PMID:Hypothermia suppresses inflammation via ERK signaling pathway in stimulated microglial cells. 1765 18

CD54 is a cell surface adhesive glycoprotein, which is expressed in most cells. Interaction between CD54 and its ligands is involved in several cellular events including activation, proliferation, and cell death and also cell-to-cell adhesion. In the present study, we found that cross-linking of CD54 on Burkitt lymphoma cell lines, Raji and Ramos, induced apoptosis. We investigated that cross-linking of CD54 on Raji and Ramos using immobilized anti-CD54 mAb (clone 6.5B5) leads to apoptosis. CD54-induced apoptosis took place in association with an increase of intracellular reactive oxygen species (ROS) and a loss of the mitochondrial membrane potential and also the activation of caspases 3 and 9, resulting in the degradation of the proteolytic poly (ADP-ribose) polymerase. Pretreatment of each N-acetyl cystein and N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (a broad caspase inhibitor) blocked apoptosis. Cross-linking of CD54 immediately induced expression of fasL, which was inhibited by pretreatment of N-acetyl cystein. NOK-1 (antagonistic anti-fasL), ZB4 (antagonistic anti-fas), and N-benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketon (caspase 8 inhibitor) effectively rescued cells from apoptosis via adjacent fas-fasL interaction but did not block ROS generation. Taken together, it is concluded that engagement of CD54 on B lymphoma cell lines by anti-CD54 mAb may trigger fasL expression through ROS generation and may subsequently induce apoptosis in adjacent fas-fasL interaction.
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PMID:Cross-linking of CD54 on Burkitt lymphoma cell line Raji and Ramos induces FasL expression by reactive oxygen species and apoptosis of adjacent cells in Fas/FasL interaction. 1789 65

To investigate the effect of anti-cytokine-based therapy in the course of diabetic cardiomyopathy, we performed a study using an anti-TNF-alpha monoclonal antibody treatment (mab) in Sprague male Dawley (SD) rats with streptozotocin-induced diabetic cardiomyopathy. Five days after streptozotocin injection, rats were treated with the anti-TNF-alpha mAb C432A for 6 weeks.At the end of the study, left ventricular (LV) function was determined by a pressure-catheter. Intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, beta2-lymphocyte-integrins(+) (CD18(+), CD11a(+), CD11b(+)), ED1/CD68(+) and cytokine (TNF-alpha, interleukin (IL)-1beta)- expressing infiltrates, total collagen content and stainings of collagen I and III were quantified by digital image analysis. LV phosphorylated and total ERK protein levels were determined by Western Blot. TNFalpha-antagonism reduced ICAM-1- and VCAM-1 expression and leukocyte infiltration to levels of non-diabetics and decreased macrophage residence by 3.3-fold compared with untreated diabetics. In addition, anti-TNF-alpha mAb-treatment decreased diabetes-induced cardiac TNF-alpha and IL-1beta expression by 2.0-fold and 1.8- fold, respectively, and reduced the ratio of phosphorylated to total ERK by 2.7-fold. The reduction in intramyocardial inflammation was associated with a 5.4-fold and 3.6-fold reduction in cardiac collagen I and III content, respectively. This was reflected by a normalization of cardiac total collagen content to levels of non-diabetics and associated with an improved LV function. TNFalpha-antagonism attenuates the development of experimental diabetic cardiomyopathy associated with a reduction of intramyocardial inflammation and cardiac fibrosis.
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PMID:Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. 1790 96

Epigallocatechin-3-O-gallate (EGCG) is the main catechin, which is derived from Camellia sinensis plant. Vascular cell adhesion molecules (VCAMs) and intercellular adhesion molecules (ICAMs) mediate the binding of inflammatory cells onto the vascular wall-promoting the early phase of atherosclerosis. In the present study, we investigated the mechanism(s) by which EGCG inhibits angiotensin II (Ang II)-induced elevation of the membrane associated VCAM-1 and ICAM-1 in human umbilical vein endothelial cells (HUVEC). Ang II induced a 40% increase of VCAM-1 and ICAM-1 in the plasma membrane. EGCG (10 to 50 microM) inhibited the effect of Ang II in a concentration-dependent manner. In parallel, the Ang II-induced elevation of the mRNA expressions of VCAM-1 and ICAM-1 in HUVEC were completely inhibited by 50 microM EGCG. Since mitogen-activated protein kinase (MAPK) families are involved in vascular inflammation in response to stressful stimuli, we investigated the effects of EGCG on the MAPK signal transduction pathway stimulated by Ang II. EGCG (30 to 50 microM) completely inhibited the Ang II-induced phosphorylation of ERK (extracellular signal-regulated kinase) 1/2 and p38 MAPK. PD98059, an inhibitor of ERK1/2 inhibited the Ang II-induced increase of VCAM-1 but not of ICAM-1 in the plasma membranes. In contrast, SB203580, an inhibitor of p38 MAPK inhibited both the Ang II-induced enrichment of ICAM-1 and VCAM-1. From these results, it may be concluded that EGCG inhibits the Ang II-induced elevation of VCAM-1 and ICAM-1 in the HUVEC plasma membranes via inhibition of the p38 MAPK and the ERK1/2 signalling pathways resulting in an inhibition of the VCAM-1 and ICAM-1 transcription.
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PMID:Epigallocatechin-3-O-gallate inhibits the angiotensin II-induced adhesion molecule expression in human umbilical vein endothelial cell via inhibition of MAPK pathways. 1798 68

Sulfur dioxide (SO(2)) is a common air pollutant, and inhaled SO(2) in airway epithelium easily forms its soluble derivatives in vivo (bisulfite and sulfite), which are toxic to the respiratory system and related to the exacerbation of asthma. In order to study the possible asthmatic molecular mechanism of SO(2) and its derivatives, the dose-response and time-response relationships of SO(2) derivatives on gene expressions of some asthma-related genes in human bronchial epithelial cells (BEP2D) were investigated. The mRNA and protein levels of EGF, EGFR, ICAM-1 and COX-2 were analyzed in BEP2D cells using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) assay, radio-immunoassay (RIA) method and Western blot analysis, respectively. The results showed that SO(2) derivatives caused the dose-dependent inductive expressions of four gene mRNA and protein in BEP2D cells. Moreover, SO(2) derivatives significantly increased the mRNA and protein levels at 0, 0.5, 1, 4 and 24h post-exposure, along with the highest inductions at 0.5h post-exposure for EGFR and COX-2 and at 4h post-exposure for EGF and ICAM-1. It was suggested that SO(2) derivatives could increase the expressions of EGF, EGFR, ICAM-1 and COX-2 on the transcription and translation levels in BEP2D cells, and result in mucus over-production and inflammation responses. This might be one of the possible mechanisms that SO(2) aggravates asthma disease.
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PMID:Effects of sulfur dioxide derivatives on four asthma-related gene expressions in human bronchial epithelial cells. 1799 55

Cells were isolated from four human amniotic membranes, and their biological characteristics analyzed during ex vivo expansion. Morphologically homogenous populations of fibroblast-like cells were obtained from the second or third passage. Under the appropriate culture conditions, these human amniotic membrane-derived mesenchymal cells (HAM) were shown to differentiate into adipocytes, osteocytes, chondrocytes and neuronal cells, as visualized by Oil Red O, von Kossa, alcian blue, anti-Neu N, and anti-Gal C antibody staining, respectively. Immunophenotype analysis of HAM cells revealed the presence of antigens for SSEA-3, SSEA-4, collagen type-I, -II, -III, -IV, -XII, fibronectin, alpha-SMA, vimentin, desmin, cytokeratin18 (CK18), HCAM-1, fibroblast surface protein, and human leukocyte antigen (HLA) ABC. ICAM-1 protein was weakly detectable, and proteins of TRA-1-60, VCAM-1, von Willebrand factor, PECAM-1, and HLA DR were not detected. HAM cells reached senescence after 14.5+/-0.9 passages, over a period of 146.8+/-8.9 days, and underwent an average of 36.9 4.7 population doublings. RT-PCR analysis showed that all four HAM cell lines consistently expressed genes of Oct-4, Rex-1, SCF, NCAM, nestin, BMP-4, GATA-4, HNF-4alpha, vimentin, and CK18, regardless of the passage number. The genes of Brachyury, FGF-5, Pax-6, and BMP2 were never expressed. Strikingly, alpha-fetoprotein (alphaFP), HLA ABC, and HLA DR genes were expressed in an earlier passage but not expressed in later passages. Telomerase activity of two HAM lines was discernable upon the third passage. These observations strongly suggest that HAM might be immune-privileged and, thus, advantageous as therapeutic cells.
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PMID:Ex vivo characteristics of human amniotic membrane-derived stem cells. 1815 18

HIV-1 Tat is considered to be one of key players to facilitate monocyte entry into the CNS, which is characteristic feature of AIDS-related encephalitis and dementia. This study was performed to determine the regulatory function of superoxide dismutase (SOD) on the HIV-1 Tat-induced signaling pathways leading to NF-kappaB activation, expression of adhesion molecules, and monocyte adhesion in CRT-MG human astroglioma cells by using cell-permeable SOD. When cell-permeable SOD was added to the culture medium of CRT-MG cells, it rapidly entered the cells in dose- and time-dependent manners. Treatment of astrocytes with cell-permeable SOD led to decrease in Tat-induced ROS generation as well as NF-kappaB activation. Cell-permeable SOD inhibited the activation of MAP kinases including ERK, JNK and p38 by HIV-1 Tat. Treatment of CRT-MG cells with cell-permeable SOD significantly inhibited protein and mRNA levels of ICAM-1 and VCAM-1 up-regulated by HIV-1 Tat, as measured by Western blot analysis and RT-PCR. Furthermore, enhanced adhesiveness of monocyte to astrocyte by HIV-1 Tat was significantly abrogated by pretreatment with cell-permeable SOD fusion proteins. These data indicate that SOD has a regulatory function for HIV-1 Tat-induced NF-kappaB activation in astrocytes and suggest that cell-permeable SOD can be used as a feasible therapeutic agent for regulation of ROS-related neurological diseases.
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PMID:Suppression of HIV-1 Tat-induced monocyte adhesiveness by a cell-permeable superoxide dismutase in astrocytes. 1816 Aug 48


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