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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen-activated protein (MAP) kinases have been suggested as potential mediators for interleukin 1beta (IL-1beta)-induced gene activation. This study investigated the role of the MAP kinases p38 and ERK2 in IL-1beta-mediated expression of the chemokine MCP-1 by human mesangial cells. Phosphorylation of p38 kinase, which is necessary for activation, increased significantly after IL-1beta treatment. p38 kinase immunoprecipitated from IL-1beta-treated cells phosphorylated target substrates to a greater extent than p38 kinase from controls. SB 203580, a selective p38 kinase inhibitor, was used to examine the role of p38 kinase in MCP-1 expression. SB 203580 decreased IL-1beta-induced MCP-1 mRNA and protein levels, but did not affect MCP-1 mRNA stability. Because NF-kappaB is necessary for MCP-1 gene expression, the effect of p38 kinase inhibition on IL-1beta induction of NF-kappaB was measured. SB 203580 (up to 25 microM) had no effect on IL-1beta-induced NF-kappaB nuclear translocation or DNA binding activity. Our previous work showed that IL-1beta also activates the MAP kinase ERK2 in human mesangial cells. PD 098059, a selective inhibitor of the ERK activating kinase MEK1, had no effect on IL-1beta-induced MCP-1 mRNA or protein levels, or on IL-1beta activation of NF-kappaB. These data indicate that p38 kinase is necessary for the induction of MCP-1 expression by IL-1beta, but is not involved at the level of cytoplasmic activation of NF-kappaB. In contrast, ERK2 does not mediate IL-1beta induced MCP-1 gene expression.
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PMID:The mitogen-activated protein kinase p38 is necesssary for interleukin 1beta-induced monocyte chemoattractant protein 1 expression by human mesangial cells. 1008 32

A finding commonly observed in human immunodeficiency virus type 1 (HIV-1)-infected patients is invasion of the brain by activated T cells and infected macrophages, eventually leading to the development of neurological disorders and HIV-1-associated dementia. The recruitment of T cells and macrophages into the brain is likely the result of chemokine expression. Indeed, earlier studies revealed that levels of different chemokines were increased in the cerebrospinal fluid of HIV-1-infected patients whereas possible triggers and cellular sources for chemokine expression in the brain remain widely undefined. As previous studies indicated that HIV-1 Tat, the retroviral transactivator, is capable of inducing a variety of cellular genes, we investigated its capacity to induce production of chemokines in astrocytes. Herein, we demonstrate that HIV-1 Tat(72aa) is a potent inducer of MCP-1, interleukin-8 (IL-8), and IP-10 expression in astrocytes. Levels of induced IP-10 protein were sufficiently high to induce chemotaxis of peripheral blood lymphocytes. In addition, Tat(72aa) induced IL-8 expression in astrocytes. IL-8 mRNA induction was seen less then 1 h after Tat(72aa) stimulation, and levels remained elevated for up to 24 h, leading to IL-8 protein production. Tat(72aa)-mediated MCP-1 and IL-8 mRNA induction was susceptible to inhibition by the MEK1/2 inhibitor UO126 but was only modestly decreased by the inclusion of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190. In contrast, Tat-mediated IP-10 mRNA induction was suppressed by SB202190 but not by the MEK1/2 inhibitor UO126. These findings indicate that MAPKs play a major role in Tat(72aa)-mediated chemokine induction in astrocytes.
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PMID:Induction of the chemokines interleukin-8 and IP-10 by human immunodeficiency virus type 1 tat in astrocytes. 1098 68

Fas transduces not only apoptotic signals through various pathways but also angiogenic and proinflammatory responses in vivo. Human glioma cells express Fas although sensitivity to Fas-mediated cell death is variable, suggesting that Fas may have functions other than apoptosis in these cells. In this study, we addressed alternative functions of Fas expressed on human gliomas by Fas ligation in three human glioma cell lines, CRT-MG, U373-MG, and U87-MG, and the in vivo expression of Fas and chemokines in human glioblastoma multiforme (GBM). Herein, we demonstrate that: (a) stimulation with agonistic anti-Fas monoclonal antibody CH-11 and human recombinant soluble Fas ligand induces expression of the CC chemokine MCP-1 and the CXC chemokine interleukin-8 by human glioma cell lines at the mRNA and protein levels in a dose- and time-dependent manner; (b) selective pharmacological inhibitors of MEK1 (U0126 and PD98059) and p38 mitogen-activated protein kinase (MAPK) (SB202190) suppress Fas-mediated chemokine expression in a dose-dependent manner; (c) Fas ligation on human glioma cells leads to activation of both extracellular signal-regulated kinases ERK1/ERK2 and p38 MAPK; and (d) GBM samples express higher levels of Fas compared with normal control brain, which correlates with increased interleukin 8 expression. These findings indicate that Fas ligation on human glioma cells leads to the selective induction of chemokine expression, which involves the ERK1/ERK2 and p38 MAPK signaling pathways. Therefore, the Fas-Fas ligand system in human brain tumors may be involved not only in apoptotic processes but also in the provocation of angiogenic and proinflammatory responses.
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PMID:Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. 1130 91

Chemokine secretion by human retinal pigment epithelium (hRPE) in response to IL-1beta and TNF-alpha occurs in infectious and noninfectious retinal diseases. In this study, the roles of p38 kinase and extracellular signal-regulated kinase (ERK) signaling pathways were investigated for IL-1beta- or TNF-alpha-induced IL-8 and MCP-1 secretion by hRPE cells. Treatment of hRPE cells with IL-1beta or TNF-alpha caused increased steady-state IL-8 and MCP-1 mRNA levels and protein secretion. Stimulation of hRPE with IL-1beta and TNF-alpha resulted in degradation of IkappaB-alpha, nuclear translocation of NF-kappaB, and prominent increases in p38 and ERK1/2 phosphorylation for as little as 3 min. The induced IL-8 and MCP-1 mRNA and proteins were partially suppressed by U0126, a specific MEK inhibitor, and by SB202190, a selective p38 inhibitor. This induction was completely blocked by simultaneous administration of the two drugs or by incubation with inhibitors for activation of NF-kappaB such as BAY11-7085, CAPE, and parthenolide. These results suggest that co-activation of MEK/ERK and p38 pathways as well as activation of NIK pathway are essential for IL-1beta- and TNF-alpha-stimulation of IL-8 and MCP-1 gene expression in hRPE cells. Furthermore, co-administration of U0126 and SB202190 did not affect the induced degradation of IkappaB-alpha and NF-kappaB nuclear translocation, indicating that NF-kappaB is activated by IL-1beta and TNF-alpha independently of activation of MEK/MAPK and p38 pathways in hRPE cells.
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PMID:Activation of p38, ERK1/2 and NIK pathways is required for IL-1beta and TNF-alpha-induced chemokine expression in human retinal pigment epithelial cells. 1142 68

Phagocytosis of apoptotic cells by macrophages results in the production of transforming growth factor-beta (TGF-beta), which plays an important role in induction of an anti-inflammatory phenotype and resolution of inflammation. In this study, we show that TGF-beta prevents pro-inflammatory cytokine production through inhibition of p38 mitogen-activated protein kinase (MAPK) and NF-kappaB. Blockade of extracellular signal-regulated kinase (ERK) signaling by the MEK-1/2 inhibitor PD 98059 reversed the inhibitory effects of TGF-beta, suggesting that cross-talk between MAPKs is essential for this response. Further investigation indicated that TGF-beta activated ERK, which in turn up-regulated MAPK phosphatase-1, thereby inactivating p38 MAPK. On the other hand, TGF-beta maintained or slightly increased production of the CC chemokine MCP-1, which is regulated predominantly by AP-1. Although SB 203580, an inhibitor of p38 MAPK, and dominant-negative p38 MAPK both increased AP-1 transcription, lack of effect of TGF-beta on lipopolysaccharide-stimulated SAPK/JNK phosphorylation along with a demonstrated inhibition of TGF-beta-induced AP-1 activation by dominant-negative Smad3 suggest that TGF-beta-stimulated AP-1 activation was not caused by inhibition of p38 MAPK but rather through the activation of Smads. Our data provide evidence that TGF-beta selectively inhibits inflammatory cytokine production through cross-talk between MAPKs.
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PMID:Cross-talk between ERK and p38 MAPK mediates selective suppression of pro-inflammatory cytokines by transforming growth factor-beta. 1184 88

Although Fas (APO-1/CD95) is expressed ubiquitously and induces cell death, it is also known to mediate other responses such as inflammation and angiogenesis in vivo. Previously, we have reported that Fas ligation induces selective expression of chemokines (IL-8 and MCP-1) in human astroglioma cells in vitro. In this study, we investigated whether Fas ligation can induce expression of other cytokines. Expression of IL-1alpha, IL-1beta, IL-6, IL-10, IL-12, IFN-beta, IFN-gamma, LT-beta, TGF-beta, TNF-a and TNF-beta mRNA levels in CRT-MG human astroglioma cells upon Fas ligation was investigated using RNase protection assay (RPA). We found that IL-6 mRNA is selectively induced upon Fas ligation, and IL-6 mRNA and protein expression was further investigated using single probe RPA and ELISA. To investigate the in vivo expression of IL-6, human brain specimens were homogenized and ELISA was performed for IL-6 expression. Herein, we demonstrate that: (1) Among these cytokines, only IL-6 was induced upon Fas ligation in a dose- and time-dependent manner; (2) A selective p38 MAP kinase inhibitor, SB202190, and a MEK inhibitor, U0126, suppressed induction of IL-6 mRNA and protein expression by Fas ligation; and (3) Glioblastoma multiforme samples (n = 11) contain significantly higher levels of IL-6 compared to those of control brains (n = 5), which correlate with increased levels of Fas. These results suggest that the Fas-FasL system may play a role in the regulation of tumor growth and survival by inducing the pleiotropic cytokine IL-6.
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PMID:Fas engagement increases expression of interleukin-6 in human glioma cells. 1194 22

Monocyte Chemoattractant Proteins (MCPs) form a distinct, structurally-related subclass of CC chemokines. They are major chemoattractants for monocytes and T lymphocytes. The MCPs bind to specific G-protein-coupled receptors, initiating a signal cascade within the cell. Though the signal transduction pathways involved in MCP-1-mediated chemotaxis have been studied, the signalling pathways through which MCP-2, -3 and -4 trigger cell migration are not established. In this study, we examined the mitogen-activated protein kinase (MAPK) activation elicited by the MCPs (1-4) and its specific role in chemotaxis. Within 2 min, the MCPs (1-4) elicited a rapid and transient activation of MAPK in peripheral blood mononuclear cells and in HEK-293 cells expressing CCR2b. U0126, an inhibitor of MAPK-kinase (MEK) activation, not only prevented extracellular signal-regulated kinase 1/2 (ERK1/2) activation but also significantly inhibited the MCP-mediated chemotaxis. PI3K inhibitors Wortmannin and LY294002 also partially inhibited the MCP-induced chemotaxis. However, these compounds did not significantly inhibit ERK1/2 activation. As PI3K inhibitors partially inhibit the MCP-mediated chemotaxis but do not significantly effect ERK1/2 activation, these data suggest that co-ordinated action of distinct signal pathways is required to produce chemokine-mediated chemotaxis.
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PMID:Leucocyte chemotaxis: Examination of mitogen-activated protein kinase and phosphoinositide 3-kinase activation by Monocyte Chemoattractant Proteins-1, -2, -3 and -4. 1196 59

Monocytes from patients with sickle cell disease (SCD) are in an activated state. However, the mechanism of activation of monocytes in SCD is not known. Our studies showed that placenta growth factor (PlGF) activated monocytes and increased mRNA levels of cytokines (tumor necrosis factor-alpha [TNF-alpha] and interleukin-1beta [IL-1beta]) and chemokines (monocyte chemotactic protein-1 [MCP-1], IL-8, and macrophage inflammatory protein-1beta [MIP-1beta]) in both normal monocytes and in the THP-1 monocytic cell line. This increase in mRNA expression of cytochemokines was also reflected in monocytes derived from subjects with SCD. We studied the PlGF-mediated downstream cellular signaling events that caused increased transcription of inflammatory cytochemokines and chemotaxis of THP-1 monocytes. PlGF-mediated cytochemokine mRNA and protein expression was inhibited by PD98059 and wortmannin, inhibitors of mitogen-activated protein kinase kinase (MAPK/MEK) kinase and phosphatidylinositol-3 (PI3) kinase, respectively, but not by SB203580, a p38 kinase inhibitor. PlGF caused a time-dependent transient increase in phosphorylation of extracellular signal-regulated kinase-1/2 (ERK-1/2), which was completely inhibited by wortmannin, indicating that activation of PI3 kinase preceded MEK activation. PlGF also induced transient phosphorylation of AKT. MEK and PI3 kinase inhibitors and antibody to Flt-1 abrogated PlGF-induced chemotaxis of THP-1 monocytes. Overexpression of a dominant-negative AKT or a dominant-negative PI3 kinase p85 subunit in THP-1 monocytes attenuated the PlGF-mediated phosphorylation of ERK-1/2, cytochemokine secretion, and chemotaxis. Taken together, these data show that activation of monocytes by PlGF occurs via activation of Flt-1, which results in activation of PI3 kinase/AKT and ERK-1/2 pathways. Therefore, we propose that increased levels of PlGF in circulation play an important role in the inflammation observed in SCD via its effects on monocytes.
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PMID:Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. 1268 30

Cell-cell contact between human retinal pigment epithelium (hRPE) cells and monocytes occurs in many retinal diseases involving blood-retinal barrier breakdown. This study investigates chemokine secretion induced by co-culture of hRPE cells and monocytes and illustrates the roles of p38 kinase, ERK, JNK/SAPK and NF-kappaB-inducing kinase signaling pathways for hRPE IL-8 and MCP-1 secretion induced in hRPE by co-culture with monocytes. Co-culture of hRPE cells with monocytes increased steady-state IL-8 and MCP-1 mRNA and protein secretion. Stimulation of hRPE cells by monocytes resulted in prominent increases in p38, ERK1/2 and JNK/SAPK phosphorolation, IkappaBalpha degradation, and NF-kappaB nuclear translocation. The induced IL-8 and MCP-1 proteins were almost completely supporessed by U0126, a specific mitogen-activated protein kinase kinase (MEK) inhibitor, or by SB203580, a selective p38 inhibitor. Chemokine secretion was completely blocked by simultaneous administration of U0126 and SB203580. Induction of IL-8 and MCP-1 was abrogated by Ro318220, an inhibitor of PKC, as well as by genistein or herbimycin A, inhibitors of PTK. In addition, anti-inflammatory drugs dexamethasone (DEX) and cyclosporin A (CSA) both blocked activation of JNKS/SAPK and the cell-cell contact induced production of hRPE IL-8 and MCP-1, while activation of p38 and ERK was only inhibited by DEX, but not by CSA. These results suggest that activation of DEX-sensitive, CSA-resistant MEK/ERK and p38 pathways, and activation of NF-kappaB, PKC, and PTK are essential for IL-8 and MCP-1 expression by hRPE cells.
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PMID:Human RPE-monocyte co-culture induces chemokine gene expression through activation of MAPK and NIK cascade. 1269 21

1. The present study was aimed to investigate the effect of benzydamine, an anti-inflammatory drug devoid of activity on arachidonic acid metabolism, on monocyte chemotaxis and to define the possible biochemical correlates of activity. 2. Benzydamine inhibited monocyte chemotaxis in response to three classes of chemoattractants: the prototypic CC-chemokine CCL2 (MCP-1), the microbial product fMLP and the complement cascade component C5a. The effect was dose-dependent with IC50's of 100, 50 and 45 microm for MCP-1/CCL2, fMLP and C5a, respectively. At the dose of 100 microm, the effect resulted in a 50+/-10% inhibition of MCP-1/CCL2-induced chemotaxis and 53+/-6 and 54+/-5% inhibitions of chemotaxis in response of fMLP and C5a, respectively (n=3). 3. Receptor expression as well as calcium fluxes in response to chemoattractants were not affected by benzydamine. 4. Benzydamine strongly inhibited chemoattractant-induced activation of the mitogen-activated protein kinase (MAPK) ERK1/2, and of its upstream activator kinase MEK1/2. ERK1/12 activation in response to chemoattractants was 89-98% inhibited by a 100 microm concentration of benzydamine with an IC50 of 30 microm. 5. Under the same experimental conditions, pretreatment with 100 microm benzydamine caused a 75-89% inhibition of p38 activation (IC50 25 microm). 6. These results indicate that the anti-inflammatory activity of benzydamine is exerted at multiple levels, including monocyte migration to chemotactic factors associated to a blockage of ERK and p38 MAPK pathways.
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PMID:Benzydamine inhibits monocyte migration and MAPK activation induced by chemotactic agonists. 1297 98


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