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 (TNFalpha), with the potential to destroy tissue, is likely to be tightly regulated. A major regulatory step is the translational repression of TNFalpha. This study evaluates whether endogenous inhibitory cytokines account for this repression. Two cell populations were isolated from peripheral blood using techniques that minimized activation, one composed primarily of monocytes and the other containing T-cells and NK-cells. When cultured without a stimulus in the presence of Abs neutralizing IL-4, IL-10, or TGFbeta, each population released large amounts of TNFalpha, reaching levels induced by PHA or LPS. Their actions were at the post-translational level since the numbers of transcripts did not change, and inhibitors of protein or RNA synthesis had no effects. When inhibitors of 38 MAP kinase and ERK were added, T-cell release of TNFalpha proved to involve both pathways while monocytes were dependent on p38 but not ERK. Changes in soluble TNF receptor levels or cell uptake of TNFalpha were not involved. This study shows that low TNFalpha secretion by resting T-cells and monocytes is maintained by endogenous inhibitors that suppress post-translational processing of TNFalpha by MAP kinases. Keeping TNFalpha levels low is critical to the non-inflammatory steady-state.
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PMID:Endogenous inhibitory cytokines repress TNFalpha secretion. 1638 87

Although TGF-beta inhibits the production of proinflammatory mediators in vitro and in vivo, its anti-inflammatory activities may be ineffective in early or severe acute inflammatory circumstances. In this study, we suggest a role for oxidative stress on TGF-beta signaling, leading to prevention of its normal anti-inflammatory effects but leaving its Smad-driven effects on cellular differentiation or matrix production unaffected. Stimulation of the RAW 264.7 macrophage cells, human or mouse alveolar macrophages with LPS led to NF-kappaB-driven production of proinflammatory mediators, which were inhibited by TGF-beta. This inhibition was prevented in the presence of hydrogen peroxide. We found that hydrogen peroxide acted by inducing p38 MAPK activation, which then prevented the ERK activation and MAPK phosphatase-1 up-regulation normally induced by TGF-beta. This was mediated through Src tyrosine kinases and protein phosphatase-1/2A. By contrast, hydrogen peroxide had no effects on TGF-beta-induced Smad2 phosphorylation and SBE-luc reporter gene transcription.
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PMID:Oxidants selectively reverse TGF-beta suppression of proinflammatory mediator production. 1639 11

Previous studies suggest that adenosine possesses anti-inflammatory properties, however, the mechanisms by which adenosine affects immune function remain unclear, particularly in the intestine. In this study, we hypothesized that adenosine directly affects pro-inflammatory gene expression in intestinal epithelial cells through modulation of NF-kappaB signaling. HT-29 cells were treated with adenosine prior to incubation with various stimuli and pro-inflammatory gene expression and signal transduction analyzed. Adenosine pretreatment resulted in a reduction in IL-8 expression and secretion in response to TNF-alpha, IL-1, LPS, and PMA. This effect was paralleled by inhibition of kappaB-driven luciferase expression and a reduction in recruitment of NF-kappaB to the IL-8 promoter. Pretreatment of HT-29 cells also resulted in reduced ERK, p38, and JNK MAPK phosphorylation, following TNF-alpha treatment. The observed effects in this study occurred independently of known surface adenosine receptors. This study identifies adenosine as a potent negative regulator of pro-inflammatory signaling in intestinal epithelial cells.
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PMID:Adenosine is a negative regulator of NF-kappaB and MAPK signaling in human intestinal epithelial cells. 1641 16

We have previously revealed that LPS can activate transcription of the IL-10 gene promoter through transcription factors Sp1, C/EBPbeta and C/EBPdelta in mouse macrophages. In this study, we determined that NF-kappaB and MAPK signal pathways, including ERK, JNK, and p38, were all involved in LPS-induced IL-10 gene expression. Treatment of cells with the pharmacological inhibitors of ERK, JNK, p38 and NF-kappaB respectively inhibited LPS-induced IL-10 protein expression in a dose-dependent manner. These inhibitors also decreased the LPS-induced IL-10 mRNA expression at a high concentration used. With transient overexpression of the IkappaB expression plasmids, or the dominant negative plasmids of ERK2, JNK, p38 together with reporter vector containing IL-10 promoter region, all four expression plasmids inhibited LPS-induced IL-10 promoter activity individually. It is known that the increase in protein and DNA binding of C/EBPbeta and delta could activate IL-10 gene expression. In this study, we also identified that all four pharmacological inhibitors inhibited the protein expression of C/EBPdelta individually, but not C/EBPbeta. In the presence of all three MAPK inhibitors, or only NF-kappaB inhibitor, LPS-induced protein expression and DNA binding of C/EBPdelta were completely inhibited simultaneously, and LPS-induced expression of IL-10 protein and mRNA was also inhibited totally. Taken together, these results suggested that LPS-induced IL-10 expression was mediated at least through the pathway of NF-kappaB- and MAPK-induced protein expression and DNA binding of C/EBPdelta.
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PMID:Lipopolysaccharide-induced transcriptional activation of interleukin-10 is mediated by MAPK- and NF-kappaB-induced CCAAT/enhancer-binding protein delta in mouse macrophages. 1641 48

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that is acutely induced by inflammatory stimuli, and the products of HO-1-mediated heme degradation have anti-inflammatory properties. In many different pathophysiologic states, the up-regulation of HO-1 has been shown to be beneficial in combating the detrimental consequences of increased inflammation. Ets transcription factors are known to be important mediators of inflammatory responses, and the ternary complex factor subfamily of Ets proteins has both transcriptional activation and repression activity. The present study demonstrates that of several ternary complex factor subfamily members, only Elk-3 represses HO-1 promoter activity in macrophages. Endotoxin administration to macrophages led to a dose-dependent decrease in endogenous Elk-3 mRNA levels, and this reduction in Elk-3 preceded the LPS-mediated up-regulation of HO-1 message. Analogous results also occurred in lung tissue of mice exposed to endotoxin. Two putative Ets binding sites (EBS1 and EBS2) are present in the downstream region of the murine HO-1 promoter (bp -125 and -93, respectively), and we recently showed that the EBS2 site is essential for HO-1 induction by endotoxin. In contrast, the present study demonstrates that the repressive effect of Elk-3 on HO-1 promoter activity is dependent on the EBS1 site. Taken together, our data reveal that Elk-3 serves as an important repressor of HO-1 gene transcription and contributes to the tight control of HO-1 gene regulation in the setting of inflammatory stimuli.
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PMID:Endotoxin-induced down-regulation of Elk-3 facilitates heme oxygenase-1 induction in macrophages. 1645

Emerging evidence suggests critical roles for APCs in suppressing immune responses. Here, we show that zymosan, a stimulus for TLR2 and dectin-1, regulates cytokine secretion in DCs and macrophages to induce immunological tolerance. First, zymosan induces DCs to secrete abundant IL-10 but little IL-6 and IL-12(p70). Induction of IL-10 is dependent on TLR2- and dectin-1-mediated activation of ERK MAPK via a mechanism independent of the activation protein 1 (AP-1) transcription factor c-Fos. Such DCs stimulate antigen-specific CD4+ T cells poorly due to IL-10 and the lack of IL-6. Second, zymosan induces F4-80+ macrophages in the splenic red pulp to secrete TGF-beta. Consistent with these effects on APCs, injection of zymosan plus OVA into mice results in OVA-specific T cells that secrete little or no Th1 or Th2 cytokines, but secrete robust levels of IL-10, and are unresponsive to challenge with OVA plus adjuvant. Finally, coinjection of zymosan with OVA plus LPS suppresses the response to OVA via a mechanism dependent on IL-10, TGF-beta, and lack of IL-6. Together, our data demonstrate that zymosan stimulates IL-10+ IL-12(p70)- IL-6low regulatory DCs and TGF-beta+ macrophages to induce immunological tolerance. These data suggest several targets for pharmacological modulation of immune responses in various clinical settings.
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PMID:Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. 1654 48

In the present study, we investigated the protective mechanism of quercetin (QUE) and its glycosides, rutin (RUT) and quercitrin (QUI), on reactive oxygen species (ROS)-dependent (H(2)O(2)) and -independent (chemical anoxia) cell death in rat glioma C6 cells. Induction of HO-1 protein expression was detected in QUE- but not RUT- or QUI-treated C6 cells, and this was prevented by cycloheximide and actinomycin D. Incubation of C6 cells with QUE, but not RUT or QUI, protected C6 cells from H(2)O(2)- and chemical anoxia-induced cytotoxicity according to the MTT and LDH release assays. Apoptotic characteristics including chromatin condensation, DNA ladders, and hypodiploid cells appeared in H(2)O(2)-and chemical anoxia-treated C6 cells, and those events were significantly suppressed by adding QUE (but not RUT or QUI). Increases in caspase 3, 8, and 9 enzyme activities with decreases in pro-PARP and pro-caspase 3 protein levels and an increase in cleaved D4-GDI protein were identified in H(2)O(2)-and chemical anoxia-treated C6 cells, and these were blocked by the addition of QUE, but not by RUT or QUI. Intracellular peroxide levels increased with H(2)O(2) and decreased with chemical anoxia, and the addition of QUE reduced the intracellular peroxide levels induced by H(2)O(2). Results of an anti-DPPH radical assay showed that QUE, RUT, and QUI dose-dependently inhibited the production of DPPH radicals in vitro; however, QUE (but not RUT or QUI) prevention of DNA damage induced by OH radicals was identified with a plasmid digestion assay. Increases in phosphorylated ERK and p53 protein expressions were detected in H(2)O(2)- but not chemical anoxia-treated C6 cells, and the addition of QUE significantly blocked H(2)O(2)-induced phosphorylated ERK and p53 protein expressions. Adding the HO-1 inhibitors, SnPP, CoPP, and ZnPP, reversed the protective effect of QUE against H(2)O(2)- and chemical anoxia-induced cell death according to the MTT assay and morphological observations. Additionally, QUE exhibited inhibitory effects on LPS/TPA-induced transformation in accordance with a decrease in MMP-9 enzyme activity and iNOS protein expression in C6 cells. Taken together, the results of this study suggest that QUE exhibits an inhibitory effect on both ROS-dependent and -independent cell death, and induction of HO-1 protein expression is involved.
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PMID:Quercetin inhibition of ROS-dependent and -independent apoptosis in rat glioma C6 cells. 1664 78

Macrophages are key regulators of immune responses. In the absence of an activating signal, murine bone marrow-derived macrophages undergo proliferation in response to their specific growth factor, namely M-CSF. The addition of bacterial LPS results in macrophage growth arrest and their engagement in a proinflammatory response. Although participation of ERKs is required for both macrophage proliferation and activation, ERK phosphorylation follows a more delayed pattern in response to activating agents. In primary macrophages, mitogen kinase phosphatase-1 (MKP-1) is a key regulator of the time course of MAPK activity. Here we showed that MKP-1 expression is dependent on Raf-1 activation. The time course of Raf-1 activation correlated with that of ERK-1/2. However, whereas ERK phosphorylation in response to M-CSF is Raf-1 dependent, in response to LPS, an alternative pathway directs the activation of these kinases. Inhibition of Raf-1 activity increased the expression of cyclin-dependent kinase inhibitors and growth arrest. In contrast, no effect was observed in the expression of proinflammatory cytokines and inducible NO synthase following LPS stimulation. The data reported here reveal new insights into how signaling determines opposing macrophage functions.
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PMID:Macrophage-colony-stimulating factor-induced proliferation and lipopolysaccharide-dependent activation of macrophages requires Raf-1 phosphorylation to induce mitogen kinase phosphatase-1 expression. 1670 17

Release of arachidonic acid from membrane glycerophospholipids by cytosolic phospholipase A2 (cPLA2) is a key step in the generation of platelet-activating factor (PAF), recognized as the most proximal mediator of inflammatory events triggered by bacterial infection. Here, we report on the role of cPLA2 in the disturbances in gastric mucin synthesis evoked by the LPS of H. pylori, a bacterium identified as a primary cause of gastric disease. Using rat gastric mucosal cells, we show that H. pylori LPS detrimental effect on gastric mucin synthesis, associated with up-regulation in PAF and endothelin-1 (ET-1) generation, was subject to suppression by a specific inhibitor of cPLA2, MAFP. Moreover, the LPS-induced changes in mucin synthesis and ET-1 generation were countered by PAF receptor antagonist, BN52020. The impedance by PAF antagonist of the LPS-induced reduction in mucin synthesis was countered by wortmannin, an inhibitor of PI3K, as well as by ERK inhibitor, PD98059. The blockade of ERK caused also inhibition of the LPS-induced cPLA2 activation and amplification in the impedance capacity of PAF antagonist on the LPS-induced ET-1 generation, while the inhibitor of PI3K had no effect. Our findings are the first to demonstrate that the detrimental consequences of H. pylori LPS on gastric mucin synthesis involve ERK-dependent cPLA2 activation that leads to up-regulation in PAF generation and ET-1 production.
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PMID:Cytosolic phospholipase A2 activation in Helicobacter pylori lipopolysaccharide-induced interference with gastric mucin synthesis. 1675

Lysophosphatidic acid (LPA) refers to a family of small phospholipid mediators that are generated in response to agonist stimulation in diverse cell types. LPA binds to G protein-coupled receptors to elicit numerous biological responses, including proliferation and inflammation. In this study, LPA production and response were characterized in a human corneal epithelial cell line, 2.040 pRSV-T. LPA levels in cells and medium are increased by exogenous 18:1 LPA (oleoyl-LPA), LPS, IL-1beta, and TNF-alpha. LPS, IL-1beta, and TNF-alpha, which mediate ocular inflammation, stimulate activation of p38, ERK, and Akt kinases in the corneal cell line. Similar responses are elicited by 18:1 LPA. Pertussis toxin (PTX) blocks LPA-induced activation of p38 and ERK but only slightly inhibits LPA-induced activation of Akt. All of the agonists tested, including LPA, stimulate proliferation of 2.040 pRSV-T cells. In these cells, both Akt and ERK pathways are important for LPA-induced proliferation. Thus PTX only partially suppresses the mitogenic response to LPA. Transcripts for the LPA receptors LPA(1)/EDG-2, LPA(2)/EDG-4, and LPA(3)/EDG-7 are expressed by the corneal cell line. Ki16425, an antagonist for LPA receptors, was used to explore the autocrine role of LPA. LPA-induced activations of p38, ERK, and Akt kinases, as well as proliferation, are inhibited by Ki16425. Ki16425 partially inhibits signal transduction and proliferation induced by the inflammatory agents tested. We conclude that LPA, produced in corneal epithelial cells in response to inflammatory agonists, contributes to mediating the mitogenic responses to these agonists in an autocrine fashion.
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PMID:Lysophosphatidic acid as a mediator for proinflammatory agonists in a human corneal epithelial cell line. 1676 Feb 61


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