Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, it has been demonstrated that macrophage inflammatory protein 1- alpha (MIP-1 alpha) is crucially involved in the development of osteolytic bone lesions in multiple myeloma (MM). The current study was designed to determine the direct effects of MIP-1 alpha on MM cells. Thus, we were able to demonstrate that MIP-1 alpha acts as a potent growth, survival, and chemotactic factor in MM cells. MIP-1 alpha-induced signaling involved activation of the AKT/protein kinase B (PKB) and the mitogen-activated protein kinase (MAPK) pathway. In addition, inhibition of AKT activation by phosphatidylinositol 3- kinase (PI3-K) inhibitors did not influence MAPK activation, suggesting that there is no cross talk between MIP-1 alpha-dependent activation of the PI3-K/AKT and extracellular-regulated kinase (ERK) pathway. Our data suggest that besides its role in development of osteolytic bone destruction, MIP-1 alpha also directly affects cell signaling pathways mediating growth, survival, and migration in MM cells and provide evidence that MIP-1 alpha might play a pivotal role in the pathogenesis of MM.
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PMID:Macrophage inflammatory protein 1-alpha (MIP-1 alpha ) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. 1250 12

The mechanisms involved in anti-inflammatory action of transforming growth factor beta (TGFbeta) have been examined by evaluating its effect on chemokine gene expression in mouse macrophages. Lipopolysaccharide (LPS)-stimulated expression of the CXC chemokines KC and MIP-2 was selectively reduced by TGFbeta in a time- and protein synthesis-dependent process. While TGFbeta had a modest effect on transcription of the KC and MIP-2 mRNAs as measured by nuclear run-on, it had no effect on LPS-stimulated luciferase expression driven by the KC promoter nor on the activation of nuclear factor kappaB (NFkappaB) DNA-binding activity and transactivation function. Interestingly, KC mRNA levels were markedly reduced by TGFbeta treatment in cells transfected with KC genomic or cDNA constructs driven from either the KC or cytomegalovirus (CMV) promoters, demonstrating the importance of sequences within the mature mRNA and suggesting that suppression may involve a posttranscriptional mechanism. In support of this possibility, LPS stimulation prolonged the half-life of KC mRNA and this stabilization response was blocked in cells treated with TGFbeta. Examination of KC mRNA expressed under control of a tetracycline-responsive promoter demonstrated that TGFbeta prevented stabilization of KC mRNA, in response to LPS but did not alter KC mRNA half-life directly. KC mRNA stabilization by LPS was dependent on activation of p38 mitogen-activated protein kinase (MAPK) activity, and TGFbeta treatment inhibited p38 MAPK activation. These findings support the hypothesis that TGFbeta-mediated suppression of chemokine gene expression involves antagonism of LPS-stimulated KC mRNA stabilization via inhibition of p38 MAPK.
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PMID:TGFbeta inhibits LPS-induced chemokine mRNA stabilization. 1271 27

In Alzheimer's disease (AD) one finds increased deposition of A beta and also an increased presence of monocytes/macrophages in the vessel wall and activated microglial cells in the brain. AD patients show increased levels of proinflammatory cytokines by activated microglia. Here we used a human monocytic THP-1 cell line as a model for microglia to delineate the cellular signaling mechanism involved in amyloid peptides (A beta(1-40) and A beta(1-42))-induced expression of inflammatory cytokines and chemokines. We observed that A beta peptides at physiological concentrations (125 nM) increased mRNA expression of cytokines (TNF-alpha, and IL-1 beta) and chemokines (monocyte chemoattractant protein-1 (MCP-1), IL-8, and macrophage inflammatory protein-1 beta (MIP-1 beta)). The cellular signaling involved activation of c-Raf, extracellular signal-regulated kinase-1 (ERK-1)/ERK-2, and c-Jun N-terminal kinase, but not p38 mitogen-activated protein kinase. This is further supported by the data showing that A beta causes phosphorylation of ERK-1/ERK-2, which, in turn, activates Elk-1. Furthermore, A beta mediated a time-dependent increase in DNA binding activity of early growth response-1 (Egr-1) and AP-1, but not of NF-kappa B and CREB. Moreover, A beta-induced Egr-1 DNA binding activity was reduced >60% in THP-1 cells transfected with small interfering RNA duplexes for Egr-1 mRNA. We show that A beta-induced expression of TNF-alpha, IL-1 beta, MCP-1, IL-8, and MIP-1 beta was abrogated in Egr-1 small inhibitory RNA-transfected cells. Our results indicate that A beta-induced expression of cytokines (TNF-alpha and IL-1 beta) and chemokines (MCP-1, IL-8, and MIP-1 beta) in THP-1 monocytes involves activation of ERK-1/ERK-2 and downstream activation of Egr-1. The inhibition of Egr-1 by Egr-1 small inhibitory RNA may represent a potential therapeutic target to ameliorate the inflammation and progression of AD.
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PMID:Amyloid peptide-induced cytokine and chemokine expression in THP-1 monocytes is blocked by small inhibitory RNA duplexes for early growth response-1 messenger RNA. 1273 78

The initiation and maintenance of airway immune responses in Th2 type allergic diseases such as asthma are dependent on the specific activation of local airway dendritic cells (DCs). The cytokine microenvironment, produced by local cells, influences the recruitment of specific subsets of immature DCs and their subsequent maturation. In the airway, DCs reside in close proximity to airway epithelial cells (AECs). We examined the ability of primary culture human bronchial epithelial cells (HBECs) to synthesize and secrete the recently described CC-chemokine, MIP-3alpha/CCL20. MIP-3alpha/CCL20 is the unique chemokine ligand for CCR6, a receptor with a restricted distribution. MIP-3alpha/CCL20 induces selective migration of DCs because CCR6 is expressed on some immature DCs but not on CD14+ DC precursors or mature DCs. HBECs were stimulated with pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin (IL)-1beta or, because of their critical role in allergic diseases, IL-4 and IL-13. Cells were also exposed to small size-fractions of ambient particulate matter. Each of these stimuli induced MIP-3alpha/CCL20 gene and protein expression. Moreover, these agents upregulated mitogen-activated protein kinase pathways in HBECs. Inhibition of the ERK1/2 pathway or p38 reduced cytokine-induced MIP-3alpha/CCL20 expression. These data suggest a mechanism by which AEC may facilitate recruitment of DC subsets to the airway.
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PMID:Airway epithelial cells release MIP-3alpha/CCL20 in response to cytokines and ambient particulate matter. 1276 Sep 62

Inefficient clearance of apoptotic cells by macrophages may cause an advanced stage of apoptosis, late apoptosis. Coculturing of macrophages with late apoptotic cells leads to high production of CXC-chemokine, IL-8, or MIP-2, a murine homologue of IL-8. However, the signaling mechanism underlying the production remains largely unknown. In this study, we examined the MAP kinase activation on coculturing of macrophages with late apoptotic cells. Extracellular signal-regulated kinase (ERK)1/2, but not p38 or c-Jun N-terminal kinase, was phosphorylated as early as 5 min after interaction of macrophages with late apoptotic cells. We then examined whether or not ERK activation is involved in the production of MIP-2 by employing selective inhibitors for MAP kinase kinase 1/2, PD98059, and U0126. These inhibitors suppressed the production of MIP-2 by macrophages at the protein and mRNA levels, whereas they did not suppress phagocytosis of late apoptotic cells, as judged on confocal microscopy. These results suggest that activation of ERK is involved in the production of MIP-2 on coculturing of macrophages with late apoptotic cells.
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PMID:Activation of extracellular signal-regulated kinase 1/2 is involved in production of CXC-chemokine by macrophages during phagocytosis of late apoptotic cells. 1282 Nov 52

Using rat peritoneal neutrophils, the complete nucleotide sequence of rat macrophage inflammatory protein-2 (MIP-2) mRNA including 5'untranslated region (UTR) and 3'UTR was determined (GenBank Accession number, AB060092). It was found that the MIP-2 mRNA has a 70 bp 5'UTR, a 303 bp coding region and a 728 bp 3'UTR which contains adenylate/uridylate (AU)-rich areas defined as AU-rich elements (AREs). Site-directed mutagenesis studies using the tetracycline-sensitive transactivator protein-expressing rat basophilic leukemia cells (RBL-2H3-TO cells) revealed that MIP-2 mRNA mutants which lack the 3'UTR are more stable than MIP-2-wild-type (wt) mRNA. A MIP-2 mRNA mutant in which some mutations were introduced to the ARE was also stable. The stability of MIP-2 mRNA was low in untreated RBL-2H3-TO cells, but it increased in the antigen-stimulated immunoglobulin E (IgE)-sensitized cells. The antigen-induced MIP-2 mRNA stabilization was counteracted by the highly specific p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 and the MAPK/ERK kinase (MEK-1) inhibitor PD98059. These findings indicate that ARE is the cis-element which mediates the rapid decay of MIP-2 mRNA, and the antigen stimulation stabilizes MIP-2 mRNA and the p38 MAPK and p44/42 MAPK pathways are involved in the antigen-induced stabilization of MIP-2 mRNA.
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PMID:Analysis of the mechanism regulating the stability of rat macrophage inflammatory protein-2 mRNA in RBL-2H3 cells. 1462 57

Positive pressure ventilation with large VTs has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human interleukin-8. The mechanisms regulating ventilation-induced cytokine production are unclear. Based on our previous in vitro model of lung cell stretch, we hypothesized that high VT ventilation-induced MIP-2 production is dependent on the activation of the c-Jun N-terminal kinase (JNK). We exposed C57BL/6 mice to high VT (30 ml/kg) or low VT (6 ml/kg) mechanical ventilation for 5 hours. High VT ventilation-induced neutrophil migration into the lung, MIP-2 protein production, MIP-2 messenger RNA expression, and JNK activation. Large VT ventilation of JNK knockout mice and pharmacologic JNK inhibition with SP600125 attenuated neutrophil sequestration and blocked MIP-2 messenger RNA expression and MIP-2 production. We conclude that lung cell stretch in vivo results in increased lung neutrophil sequestration and increased MIP-2 production, which was, at least in part, dependent upon the JNK pathway.
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PMID:Ventilation-induced neutrophil infiltration depends on c-Jun N-terminal kinase. 1464 30

The proinflammatory response of infected macrophages is an important early host defense mechanism against mycobacterial infection. Mycobacteria have been demonstrated to induce proinflammatory gene transcription through the Toll-like receptors, (TLR)2 and TLR 4, which initiate signaling cascades leading to nuclear factor (NF)-kappaB activation. The main transduction pathway responsible for NF-kappaB activation has been established and involves the MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor-6, NF-kappaB-inducing kinase, and inhibitor of kappaB kinase complex. The role of other kinase cascades triggered by mycobacteria in the NF-kappaB activation is less clear. We herein examine the role of the mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI-3K) cascades in the expression of the bacillus Calmette-Guerin (BCG) mycobacteria-induced NF-kappaB-dependent genes, macrophage-inflammatory protein-2 (MIP-2) and inducible nitric oxide (NO) synthase. Specific pharmacological inhibition of the PI-3K, c-jun-N-terminal kinase (JNK), and to a smaller extent, p38 MAPK but not extracellular-regulated kinase (ERK), suppressed NF-kappaB-dependent reporter gene transcription and MIP-2 and NO secretion in BCG-induced RAW264.7 macrophages. A similar effect was obtained following molecular inhibition of JNK via JNK-interacting protein-1 overexpression. In addition, a kinase-dead mutant of MEK kinase-1, the up-stream regulator of JNK, also proved to be a potent inhibitor of NF-kappaB-reporter activity. The effect of inhibitors was mediated by the down-regulation of NF-kappaB transcription activity and without effecting its nuclear translocation. These data suggest an indirect mechanism of the NF-kappaB regulation by these kinases, probably through p65 phosphorylation and improved binding to the p300 transcription coactivator. The data obtained demonstrate that PI-3K, JNK, and p38 MAPK activation by mycobacteria enhance NF-kappaB-driven gene expression contributing to the proinflammatory macrophage response.
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PMID:Activation of phosphatidylinositol 3-kinase and c-Jun-N-terminal kinase cascades enhances NF-kappaB-dependent gene transcription in BCG-stimulated macrophages through promotion of p65/p300 binding. 1474 34

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

Intracerebral infection with Theiler's virus induces a demyelinating disease that resembles human MS. In order to delineate the early events in virus-induced inflammatory disease, we have analyzed chemokine gene activation following Theiler's murine encephalomyelitis virus (TMEV) infection. Infection of primary astrocyte cultures results in activation of various chemokine genes (GRO-1, MCP-1, MCP-5, MIP-1alpha, MIP-1beta, MIP-2, RANTES, IP-10 and MCP-3) that are important in the initiation of an inflammatory response. As early as 1-3 h after TMEV infection, chemokine gene expression is strongly activated. In addition, proinflammatory cytokines do not interfere with TMEV-induced chemokine gene expression and some cytokines may function synergistically for virus-induced upregulation of chemokine gene expression. Chemokine gene activation by TMEV appears to be largely independent of the IFNalphabeta pathway and partly dependent on dsRNA-dependent protein kinase (PKR) and MAP kinase pathways. However, TMEV-induced chemokine gene expression is completely dependent on the NFkappaB pathway. These results strongly suggest that the expression of select chemokine genes upon TMEV infection is activated via the NFkappaB pathway, similar to that of proinflammatory cytokine genes, and these cellular gene products appear to synergistically promote inflammatory responses in the CNS.
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PMID:The scope and activation mechanisms of chemokine gene expression in primary astrocytes following infection with Theiler's virus. 1502 72


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