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)

Tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine, is produced abundantly by monocytes and macrophages. We have compared LPS-stimulated TNF-alpha production and regulation in freshly isolated human monocytes and macrophages differentiated in vitro. A significant increase in LPS-induced TNF-alpha protein secretion was observed in macrophages over freshly isolated monocytes without comparable differences in TNF-alpha mRNA induction. Polysome gradient analysis showed polysome-mRNA distribution did not change, whereas TNF-alpha mRNA stability increased in macrophages. Tristetraprolin mRNA expression was constitutive and decreased with differentiation-linked kinetics. Blockable LPS-inducible MAP kinase activity (p38, ERK) affected TNF-alpha biosynthesis differentially at the transcriptional and post-transcriptional level throughout the culture period. We suggest that the increase in TNF-alpha secretion in macrophages relates to changes in post-transcriptional processing, which is regulated indirectly by the expression of RNA-binding proteins. Changes in gene expression throughout monocytic differentiation equip the cell to act as a more potent producer of this proinflammatory cytokine.
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PMID:Post-transcriptional regulation of TNF-alpha during in vitro differentiation of human monocytes/macrophages in primary culture. 1205 Jan 89

TNF-alpha is a mediator of lethality in experimental infections by group B streptococcus (GBS), an important human pathogen. Little is known of signal transduction pathways involved in GBS-induced TNF-alpha production. Here we investigate the role of mitogen-activated protein kinases (MAPKs) and NF-kappa B in TNF-alpha production by human monocytes stimulated with GBS or LPS, used as a positive control. Western blot analysis of cell lysates indicates that extracellular signal-regulated kinase 1/2 (ERK 1/2), p38, and c-Jun N-terminal kinase MAPKs, as well as I kappa B alpha, became phosphorylated, and hence activated, in both LPS- and GBS-stimulated monocytes. The kinetics of these phosphorylation events, as well as those of TNF-alpha production, were delayed by 30-60 min in GBS-stimulated, relative to LPS-stimulated, monocytes. Selective inhibitors of ERK 1/2 (PD98059 or U0126), p38 (SB203580), or NF-kappa B (caffeic acid phenetyl ester (CAPE)) could all significantly reduce TNF-alpha production, although none of the inhibitors used alone was able to completely prevent TNF-alpha release. However, this was completely blocked by combinations of the inhibitors, including PD98059-SB203580, PD98059-CAPE, or SB203580-CAPE combinations, in both LPS- and GBS-stimulated monocytes. In conclusion, our data indicate that the simultaneous activation of multiple pathways, including NF-kappa B, ERK 1/2, and p38 MAPKs, is required to induce maximal TNF-alpha production. Accordingly, in septic shock caused by either GBS or Gram-negative bacteria, complete inhibition of TNF-alpha release may require treatment with drugs or drug combinations capable of inhibiting multiple activation pathways.
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PMID:Mitogen-activated protein kinases and NF-kappa B are involved in TNF-alpha responses to group B streptococci. 1213 65

1: We have previously shown that the flavonoid luteolin inhibits the expression of pro-inflammatory molecules induced by LPS. In the present study we tested the ability of luteolin to block signalling pathways implicated in LPS-induced inflammatory gene expression in macrophages. 2: Exposure of the murine macrophage cell line RAW 264.7 to LPS increased phosphorylation of the mitogen-activated protein kinase family members ERK1/2, p38 and JNK1/2 in a time-dependent manner. Pretreatment of RAW 264.7 with luteolin inhibited the LPS-induced ERK1/2 and p38, but not JNK1/2, phosphorylation, and blocked the LPS-induced TNF-alpha release. 3: To investigate which of these pathways contribute to the inhibitory effects of luteolin on TNF-alpha release, cells were pretreated with pharmacological inhibitors of these pathways; PD98059 and SB203580 when used alone failed to inhibit TNF-alpha release, whereas pretreatment with both agents attenuated TNF-alpha release. 4: We have previously shown that luteolin blocks Akt phosphorylation in response to LPS in RAW 264.7 macrophages. To determine the role of Akt in TNF-alpha release, cells were transiently transfected with a dominant negative form of Akt (K179M). Overexpression of K179M Akt did not alter LPS-induced TNF-alpha release, suggesting that inhibition of this kinase does not mediate the inhibitory action of luteolin. 5: In addition, DRB (a pharmacological inhibitor of CK2) blocked TNF-alpha release in a concentration-dependent manner, whereas co-treatment of cells with luteolin and DRB did not have an additive effect. 6: We conclude that luteolin interferes with LPS signalling by reducing the activation of several MAPK family members and that its inhibitory action on TNF-alpha release correlates with inhibition of ERK, p38 and CK2 activation.
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PMID:Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin. 1214 6

Reduction of neutrophil apoptosis represents a major cause for granulocytosis and increases the destructive potential of theses cells during systemic inflammatory response syndrome (SIRS) and sepsis. In this light, the role of protein kinases for the regulation of altered neutrophil apoptosis under infectious conditions was investigated. Neutrophils, obtained from patients with severe sepsis (n = 18), were incubated ex vivowith either LPS (1 microg/mL) or interferon-gamma (IFN-gamma; 10 ng/mL) for 16 h. Apoptosis was determined by propidium iodine (PI) staining of DNA fragments and was compared with the rate of spontaneous apoptosis. Tyrosine kinases were inhibited by herbimycin (1 microM), the mitogen-activated protein (MAP) kinase ERK was inhibited with PD98059 (50 microM), and p38 MAP kinase was inhibited with SB203580 (5 microM). Herbimycin reconstituted LPS-reduced apoptosis in neutrophils from controls (39.9 +/- 3.8%) and patients (20.8 +/- 2.8%) to levels seen in spontaneous apoptosis (70.9 +/- 2.8% and 40.7 +/- 3.7%, respectively). Inhibition of the ERK kinase yielded similar results, whereas SB203580 had no effect on LPS-reduced apoptosis. However, inhibition of p38 partially reconstituted IFN-gamma-reduced apoptosis (51.3 +/- 7.7% and 25.6 +/- 5.8%) and increased spontaneous apoptosis (82.4 +/- 3.3% and 42.0 +/- 5.8%) in controls and patients, respectively. Western blot analysis revealed phosphorylation of both MAP kinases by LPS, but not by IFN-gamma. Inhibition of MAP kinases did not augment neutrophil apoptosis in patients to the level seen in controls, indicating that other mechanisms must be involved in the regulation of neutrophil apoptosis. Although the ERK kinase regulates LPS-induced reduction of apoptosis, the p38 MAP kinase might be involved in IFN-gamma signaling and the feedback regulation of neutrophil apoptosis.
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PMID:Activation of mitogen-activated protein kinases during granulocyte apoptosis in patients with severe sepsis. 1241 17

The action mechanisms of several chemopreventive agents derived from herbal medicine and edible plants have become attractive issues in cancer research. Tea is the most widely consumed beverage worldwide. Recently, the cancer chemopreventive actions of tea have been intensively investigated. It have been demonstrated that the active principles of tea were attributed to their tea polyphenols. Recently, tremendous progress has been made in elucidating the molecular mechanisms of cancer chemoprevention by tea and tea polyphenols. The suppression of various tumor biomarkers including growth factor receptor tyrosine kinases, cytokine receptor kinases, PI3K, phosphatases, ras, raf, MAPK cascades, N x FB, I x B kinase, PKA, PKB, PKC, c-jun, c-fos, c-myc, cdks, cyclins, and related transducing proteins by tea polyphenols has been studied in our laboratory and others. The I x B kinase (IKK) activity in LPS-activated murine macrophages (RAW 264.7 cells) was found to be inhibited by various tea polyphenols including (-) epigallocatechin-3-gallate (EGCG), theaflavin (TF-1), theaflavin-3-gallate (TF-2) and theaflavin-3,3'-digallate (TF-3). TF-3 inhibited IKK activity in activated macrophages more strongly than did the other tea polyphenols. TF-3 inhibited both IKK1 and IKK2 activity and prevented the degradation of I x B x and I x B x in activated macrophage cells. The results suggested that the inhibition of IKK activity by TF-3 and other tea polyphenols could occur by a direct effect on IKKs or on upstream events in the signal transduction pathway. TF-3 and other tea polyphenols blocked phosphorylation of IB from the cytosolic fraction, inhibited NFB activity and inhibited increases in inducible nitric oxide synthase levels in activated macrophage. TF-3 and other tea polyphenols also inhibited strongly the activities of xanthine oxidase, cyclooxygenase, EGF-receptor tyrosine kinase and protein kinase C. These results suggest that TF-3 and other tea polyphenols may exert their cancer chemoprevention through suppressing tumor promotion and inflammation by blocking signal transduction. The mechanisms of this inhibition may be due to the blockade of the mitogenic and differentiating signals through modulating EGFR function, MAPK cascades, NFkappaB activation as well as c-myc, c-jun and c-fos expression.
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PMID:Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways. 1243 85

For the first time, the current series of studies provide a possible pathophysiologic mechanism of NO-induced ocular surface disease. NO is present in tear and aqueous humor and is suspected of having an important physiological role in maintaining normal homeostasis of the ocular surface. NO concentrations are higher in aqueous humor compared to tears, though some variability exists between different species. When inflammation was induced by PTK wounding or LPS, three forms of NOS expression were seen in corneal cells. Each isoform of NOS was expressed uniquely according to the specific location of inflammation. When concentrations of NO peaked, the levels of iNOS were markedly increased in fibroblasts and inflammatory cells. The correlation between NO and inflammation was confirmed by treatment with NOS inhibitor, which abrogated the amount of both NO and inflammation. The tissue damage by NO was measured by nitrotyrosine formation. Damage was detected mainly in inflammatory cells, especially those localized in and around the limbal vessel. It is likely that expression of iNOS in limbal fibroblasts has other roles related to survival of limbal stem cells and fibroblasts as well. Because the main source of NO are fibroblasts, we were able to determine the effect of various concentrations of NO on cell viability using a fibroblast culture system. Cell viability increased in dose dependent manner from 10 microM to 500 microM of the NO generator SNAP, but decreased at concentrations above 1000 microM, suggesting that the in vivo mechanism of cell death was indirect, through specific biologic pathways. Therefore, the pathophysiological mechanism of NO action is bimodal with a toxicological component in ocular surface diseases. Furthermore, its concentration and interaction with other oxygen mediators appear to vary depending on the degree of inflammation.
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PMID:The role of nitric oxide in ocular surface diseases. 1261 78

Quercetin is a flavonoid molecule ubiquitous in nature and functions as an anti-oxidant and anti-inflammatory agent with little toxicity in vivo and in vitro. Dose- and time-dependent effect of quercetin has been investigated on proinflammatory cytokine expression and NO production, focusing on its effects on the MAP kinases and the NF-kappaB signal transduction pathways in LPS-stimulated RAW 264.7 cells by using RT-PCR and immunoblotting. Quercetin strongly reduced activation of phosphorylated ERK kinase and p38 MAP kinase but not JNK MAP kinase by LPS treatment. In addition, quercetin treatment inhibited NF-kappaB activation through stabilization of the NF-kappaB/IkappaB complex and IkappaB degradation and proinflammatory cytokines and NO/iNOS expression. Quercetin may exert its anti-inflammatory and immunomodulatory properties in the effect molecules such as proinflammatory cytokines and NO/iNOS by suppressing the activation of ERK and p38 MAP kinase, and NF-kappaB/IkappaB signal transduction pathways.
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PMID:Quercetin suppresses proinflammatory cytokines production through MAP kinases andNF-kappaB pathway in lipopolysaccharide-stimulated macrophage. 1261 1

Endotoxin (lipopolysaccharide, LPS) inducible cytokine release by human whole blood is increasingly used to model inflammatory responses in vitro, to detect the presence of pyrogenic contaminations as well as to monitor disease states or immunomodulatory treatments ex vivo. However, the LPS-stimulated blood model primarily allows the assessment of monocyte responses. Here, a whole blood model was established which allows assessment of lymphocyte responses. Four different superantigens, namely staphylococcal enterotoxin A and B (SEA, SEB), toxic shock syndrome toxin-1 (TSST-1) or streptococcal exotoxin A (SPEA) were tested with respect to the induction of lymphokine release. All superantigens were capable of inducing significant amounts of the lymphokines interferon-gamma (IFNgamma), interleukin 2 (IL-2), IL-4, IL-5, IL-13 and tumor necrosis factor beta (TNFbeta) after 72 h of incubation. Concentration-dependencies and kinetics were determined. Blood from 160 healthy donors was used to assess the variability of SEB-inducible lymphokine release. Interindividual differences were more pronounced compared to LPS-inducible monokine release. However, the individual response was maintained when blood from six donors was tested once a week for 8 weeks, suggesting that the individual response represents a donor characteristic. The model appears to be suitable for the evaluation of immunomodulatory agents in vitro as well as ex vivo.
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PMID:A model of human whole blood lymphokine release for in vitro and ex vivo use. 1266 71

TLR4 and MD-2 are necessary for conferring cellular responsiveness to LPS. Prior exposure to LPS induces a transient state of cell refractoriness to subsequent LPS re-stimulation, known as 'endotoxin tolerance'. While induction of LPS tolerance has been reported to correlate with down-regulation of cell surface expression of TLR4/MD-2, other mechanisms of LPS tolerance have been revealed that target intracellular intermediates downstream of the TLR4/MD-2 complex. In this study, we sought to examine whether endotoxin tolerance could be induced under conditions where expression of TLR4 and MD-2 proteins is not affected by LPS. Human HEK 293T cells are completely unresponsive to LPS, but acquire high LPS sensitivity following transient transfection with CD14, TLR4, and MD-2 (293T/CD14/TLR4/MD-2 cells), as judged by NF-kappaB activation, ERK 1/2 phosphorylation, and TNF-alpha gene expression. Prior exposure of 293T/CD14/TLR4/MD-2 cells to LPS resulted in a significant decrease of LPS-mediated responses, yet failed to affect expression levels of TLR4 and MD-2. Thus, altered expression and/or function of intracellular mediators downstream of the TLR4/MD-2 complex play an important role in mediating LPS tolerance.
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PMID:Overexpression of CD14, TLR4, and MD-2 in HEK 293T cells does not prevent induction of in vitro endotoxin tolerance. 1269 21

Signal transduction events in monocyte matrix metalloproteinase (MMP) production have been shown to include a PGE(2)-cAMP-dependent step. To determine earlier pathway components, we examined the role of mitogen-activated protein kinases (MAPKs) in the regulation of monocyte MMP-1 and MMP-9, two major MMPs induced by LPS. Stimulation with LPS resulted in the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen-activated kinase p38. The p38-specific inhibitor SB203580 suppressed p38 activity and MMP-1 mRNA and protein, but increased ERK activity and MMP-9 mRNA and protein. In contrast, the MAPK kinase 1/2-specific inhibitor PD98059 inhibited MMP-1 and MMP-9. However, both MAPK inhibitors decreased the production of cyclooxygenase-2 and PGE(2), but only the inhibition of MMP-1 by SB203580 was reversed by PGE(2) or dibutyryl cAMP. Examination of the effect of these MAPK inhibitors on the promoters of MMP-1 and MMP-9 revealed that PD98059 inhibited the binding of transcription factors to all of the MMP promoter-specific complementary oligonucleotides tested. However, SB203580 only inhibited the binding of MMP-1-specific CREB and SP 1 oligonucleotides, which was reversed by PGE(2). Additionally, SB203580 enhanced transcription factor binding to the oligonucleotides complementary to a NF-kappaB site in the promoter of MMP-9. Thus, LPS induction of MMP-1 production by monocytes is regulated by both ERK1/2 and p38, whereas MMP-9 stimulation occurred mainly through the ERK1/2 pathway. Moreover, p38 regulates MMP-1 mainly through a PGE(2)-dependent pathway, whereas ERK1/2-mediated MMP-1 and MMP-9 production involves the activation of additional MMP promoter sites through a PGE(2)-independent mechanism.
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PMID:Differential regulation of lipopolysaccharide-induced monocyte matrix metalloproteinase (MMP)-1 and MMP-9 by p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. 1279 56


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