Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type IIA secretory phospholipase A(2) (sPLA(2)) is an acute-phase reactant that plays a role in atherogenesis and is expressed in atherosclerotic arterial walls displaying inflammatory features. This generates a relevant question addressing the biological effects of this enzyme on monocytic cells, in view of the role of these cells in the inflammatory process associated with atherosclerosis. sPLA(2) produced a mild activation of the p42 mitogen-activated protein module of the mitogen-activated protein kinase (MAPK) cascade and a prominent activation of c-Jun N-terminal kinase in THP-1 monocytes. This activation showed both an early and a late peak, different from that elicited by tumor necrosis factor-alpha (TNF-alpha), which only showed the first peak. This was accompanied by activation of arachidonate metabolism, as judged from both the activation of the cytosolic phospholipase A(2) (cPLA(2)) and the induction of cyclooxygenase-2 (COX-2) expression. sPLA(2) also elicited the production of monocyte chemoattractant protein-1 (MCP-1) and showed a synergistic effect with TNF-alpha on both COX-2 induction and MCP-1 production. sPLA(2) upregulated the expression of Fas ligand at the cell surface, but it did not influence Fas expression nor cell survival of monocytes. In summary, these data indicate that some of the atherogenic effects of sPLA(2) can be exerted by engagement of an sPLA(2)-binding structure on monocytic cells, most probably the M-type receptor for sPLA(2), which produces the activation of the MAPK cascade, induces a proinflammatory phenotype, and upregulates the cell surface expression of Fas ligand.
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PMID:Secretory phospholipase A(2) elicits proinflammatory changes and upregulates the surface expression of fas ligand in monocytic cells: potential relevance for atherogenesis. 1178 16

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), have been shown to stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent data suggest that steady laminar flow decreases EC apoptosis and blocks TNF-mediated EC activation. EC apoptosis is likely important in the process termed "plaque erosion" that leads to platelet aggregation. Steady laminar flow inhibits EC apoptosis by preventing cell cycle entry, by increasing antioxidant mechanisms (e.g., superoxide dismutase), and by stimulating nitric oxide-dependent protective pathways that involve enzymes PI3-kinase and Akt. Conversely, our laboratory has identified nitric oxide-independent mechanisms that limit TNF signal transduction. TNF regulates gene expression in EC, in part, by stimulating mitogen-activated protein kinases (MAPK) which phosphorylate transcription factors. We hypothesized that fluid shear stress modulates TNF effects on EC by inhibiting TNF-mediated activation of MAP kinases. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm2) on TNF-stimulated activity of two MAP kinases: extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK). Flow alone stimulated ERK1/2 activity, but decreased JNK activity compared to static controls. TNF (10 ng/ml) alone activated both ERK1/2 and JNK maximally at 15 minutes in human umbilical vein EC (HUVEC). Pre-exposing HUVEC for 10 minutes to flow inhibited TNF activation of JNK by 46%, but it had no significant effect on ERK1/2 activation. Incubation of EC with PD98059, a specific mitogen-activated protein kinase kinase inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Flow-mediated inhibition of JNK was unaffected by 0.1 mM L-nitroarginine, 100 pM 8-bromo-cyclic GMP, or 100 microM 8-bromo-cyclic AMP. Transfection studies with dominant negative constructs of the protein kinase MEK1 and MEK5 suggested an important role for BMK1 in flow-mediated regulation of TNF signals. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms.
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PMID:Endothelial atheroprotective and anti-inflammatory mechanisms. 1179 13

Recently, it has been demonstrated that the fat-derived protein adiponectin is an important insulin-sensitizing adipocytokine which is downregulated in insulin resistance and obesity and replenishment of which in adiponectin-deficient states improves insulin sensitivity. To clarify the regulation of adiponectin gene expression, 3T3-L1 adipocytes were treated with various hormones known to induce insulin resistance in vivo and adiponectin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, treatment of 3T3-L1 cells with 100 nM insulin, 10 ng/ml tumor necrosis factor (TNF) alpha, or 100 nM dexamethasone for 16 h suppressed adiponectin gene expression by about 50 to 85% while angiotensin 2, growth hormone, and triiodothyronine did not have any effect. Furthermore, insulin reduced the level of adiponectin mRNA in a dose- and time-dependent fashion with inhibition detectable at concentrations as low as 10 nM insulin and as early as 4 h after effector addition. The inhibitory effect of insulin was partially reversed by pretreatment of 3T3-L1 cells with pharmacological inhibitors of p44/42 mitogen-activated protein (MAP) kinase, phosphatidylinositol (PI) 3-kinase, and p70S6 kinase. Moreover, the negative effects of insulin, TNFalpha, and dexamethasone on adiponectin gene expression could be completely reversed by withdrawal of the hormones for 24 h. Taken together, our results suggest that adiponectin gene expression is reversibly downregulated by insulin, TNFalpha, and dexamethasone. The data support the concept of adiponectin being an important selectively controlled modulator of insulin sensitivity.
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PMID:Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. 1179 86

Nonenzymatic glycation is increased in diabetes. The role of advanced glycation end products has been implicated in many of the complications of diabetes, whereas the effects of early-glycation Amadori-modified proteins on vascular cells alone are poorly defined. In the present study, we show that glycated serum albumin (GSA) induces a parallel activation of the redox-responsive transcription factors (nuclear factor kappaB) and AP-1 and increases activity of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38 MAPK in vascular smooth muscle cells (VSMCs). GSA increased expression of early response genes, c-fos and c-jun, and inflammatory genes, monocyte chemoattractant peptide (MCP-1), and interleukin (IL)-6. These effects were comparable to bacterial lipopolysaccharide, tumor necrosis factor-alphaa, (TNF-alphaa), IL-1alphab, angiotensin II, epidermal growth factor, and the phorbol ester PMA. One of signaling pathways by which GSA activates VSMCs appears to be via nuclear factor kappaB activation, leading to induction of MCP-1 and IL-6 gene expression, comparable to the effects of lipopolysaccharide, TNF-alphaa, and IL-1alphab. Another signaling cascade by which GSA activates VSMCs is the ERK-->c-Fos-->AP-1 pathway, which may lead to stimulation of cell proliferation and migration. These effects are comparable to the effects of angiotensin II, epidermal growth factor, and PMA. Incubation of VSMCs with the antioxidant N-acetylcysteine suppressed GSA-elicited mRNA induction of MCP-1 and IL-6. Inhibition of p38 MAPK but not ERK caused attenuation of MCP-1 and IL-6 mRNA induction. Finally, GSA caused a significant stimulation of VSMC growth and migration. These findings suggest that GSA may play a role in diabetic atherogenesis by activating VSMCs, leading to induction of inflammatory mediators in the vessel wall, as well as proliferation and migration of VSMCs.
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PMID:Vascular smooth muscle cell activation by glycated albumin (Amadori adducts). 1179 73

Although ethanol is known to sensitize hepatocytes to tumor necrosis factor (TNF) lethality, the mechanisms involved remain controversial. Recently, others have shown that adding TNFalpha to cultures of ethanol-pretreated hepatocytes provokes the mitochondrial permeability transition, cytochrome c release, procaspase 3 activation, and apoptosis. Although this demonstrates that ethanol can sensitize hepatocytes to TNF-mediated apoptosis, the hepatic inflammation and ballooning hepatocyte degeneration that typify alcohol-induced liver injury suggest that other mechanisms might predominate in vivo. To evaluate this possibility, acute responses to lipopolysaccharide (LPS), a potent inducer of TNFalpha, were compared in mice that had been fed either an ethanol-containing or control diet for 5 weeks. Despite enhanced induction of cytokines such as interleukin (IL)-10, IL-15, and IL-6 that protect hepatocytes from apoptosis, ethanol-fed mice exhibited a 4-5-fold increase in serum alanine aminotransferase after LPS, confirming increased liver injury. Six h post-LPS histology also differed notably in the two groups, with control livers demonstrating only scattered apoptotic hepatocytes, whereas ethanol-exposed livers had large foci of ballooned hepatocytes, inflammation, and scattered hemorrhage. No caspase 3 activity was noted during the initial 6 h after LPS in ethanol-fed mice, but this tripled by 1.5 h after LPS in controls. Procaspase 8 cleavage and activity of the apoptosis-associated kinase, Jun N-terminal kinase, were also greater in controls. In contrast, ethanol exposure did not inhibit activation of cytoprotective mitogen-activated protein kinases and AKT or attenuate induction of the anti-apoptotic factors NF-kappaB and inducible nitric oxide synthase. Consistent with these responses, neither cytochrome c release, an early apoptotic response, nor hepatic oligonucleosomal DNA fragmentation, the ultimate consequence of apoptosis, was increased by ethanol. Thus, ethanol exacerbates TNF-related hepatotoxicity in vivo without enhancing caspase 3-dependent apoptosis.
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PMID:Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation. 1181 69

Activation of microglia, the resident macrophages in the CNS, plays a significant role in neuronal death or degeneration in a broad spectrum of CNS disorders. Recent studies indicate that nanomolar concentrations of the serine protease, thrombin, can activate microglia in culture. However, in contrast to other neural cells responsive to thrombin, the participation of novel protease-activated receptors (PARs), such as the prototypic thrombin receptor PAR1, in thrombin-induced microglial activation was cast in doubt. In this report, by utilizing primary microglial cultures from PAR1 knockout (PAR1-/-) mice, application of the PAR1 active peptide TRAP-6 (SFLLRN) in comparison to a scrambled peptide (LFLNR), we have unambiguously demonstrated that murine microglia constitutively express PAR1 mRNA that is translated into fully functional protein. Activation of the microglial PAR1 induces a rapid cytosolic free [Ca2+]i increase and transient activation of both p38 and p44/42 mitogen-activated protein kinases. Moreover, although in part, this PAR1 activation directly contributes to thrombin-induced microglial proliferation. Furthermore, although not directly inducing tumor necrosis factor-alpha (TNF-alpha) release, PAR1 activation up-regulates microglial CD40 expression and potentiates CD40 ligand-induced TNF-alpha production, thus indirectly contributing to microglial activation. Taken together, these results demonstrate an essential role of PAR1 in thrombin-induced microglial activation. In addition, strategies aimed at blocking thrombin signaling through PAR1 may be therapeutically valuable for diseases associated with cerebral vascular damage and significant inflammation with microglial activation.
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PMID:Participation of protease-activated receptor-1 in thrombin-induced microglial activation. 1184 73

To determine the apoptotic signaling pathway which tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) induced, we investigated the contribution of reactive oxygen species (ROS), p38 mitogen-activated protein (MAP) kinase and caspases in human adenocarcinoma HeLa cells. Here we show that upon TRAIL/Apo2L exposure there was pronounced ROS accumulation and activation of p38 MAP kinase, and that activation of caspases and apoptosis followed. Pretreatment with antioxidants such as glutathione or estrogen attenuated TRAIL/Apo2L-induced apoptosis through a reduction of ROS generation and diminished p38 MAP kinase and caspase activation. The p38 MAP kinase inhibitor SB203580 prevented apoptosis through a blockage of caspase activation, although ROS generation was not attenuated. Furthermore, the pan-caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethyl ketone fully prevented apoptosis, while neither ROS accumulation nor p38 MAP kinase activation were affected. Therefore, our results suggest that TRAIL/Apo2L-induced apoptosis is mediated by ROS-activated p38 MAP kinase followed by caspase activation in HeLa cells.
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PMID:The involvement of reactive oxygen species (ROS) and p38 mitogen-activated protein (MAP) kinase in TRAIL/Apo2L-induced apoptosis. 1185 2

Human airway smooth muscle (HASM) cells express interleukin (IL)-13 and IL-4 receptors and respond to these cytokines with signal transducer and activator of transcription-6 and extracellular signal-regulated kinase (ERK) activation. The purpose of this study was to determine whether IL-13 and/or IL-4 influence eotaxin release in HASM cells and whether the ERK mitogen-activated protein (MAP) kinase pathway is involved in these events. Eotaxin release into HASM cell supernatants was assayed by ELISA, and eotaxin mRNA expression was determined by Northern blot analysis. Pretreatment with either IL-13 or IL-4 resulted in a concentration- and time-dependent release of eotaxin, although IL-4 was more effective. Eotaxin release was approximately twice baseline after treatment with 50 ng/ml IL-13 or IL-4 (P < 0.001). IL-13 and IL-4 also acted synergistically with tumor necrosis factor (TNF)-alpha to induce eotaxin release: TNF-alpha alone (10 ng/ml for 24 h) resulted in an approximately fourfold increase in eotaxin release, whereas TNF-alpha in combination with IL-13 or IL-4 resulted in 10- or 20-fold increases (P < 0.05). Similar results were obtained for eotaxin mRNA expression. Pretreatment with either U-0126 (10 microM) or PD-98059 (30 microM), both inhibitors of MAP/ERK kinase, the enzyme upstream of ERK, inhibited IL-13- or IL-4-induced eotaxin release (P < 0.05). U-0126 also inhibited IL-13, and TNF-alpha induced mRNA expression. Our results indicate that IL-13 and IL-4 cause eotaxin release in HASM cells through a mechanism that, in part, involves ERK activation and suggest that the smooth muscle may be an important source of chemokines leading to eosinophil recruitment in asthma.
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PMID:IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK. 1188 Mar 12

ATP-binding cassette (ABC) transporters are a large family of proteins whose role is to translocate various substances across biological membranes. They include the Tangier disease protein ABC1, sulfonylurea receptors (SUR), multidrug resistance protein (MDR), and cystic fibrosis transmembrane regulator (CFTR). In the current study, we investigated the involvement of ABC transporters in the regulation of lipopolysaccharide (LPS) and/or interferon (IFN)-gamma-induced interleukin (IL)-12 p40 and tumor necrosis factor (TNF)-alpha production, nitric oxide formation, as well as major histocompatibility complex II up-regulation in macrophages. The general ABC transporter inhibitor glibenclamide suppressed both IL-12 p40 and nitric oxide production. However, glibenclamide failed to affect the production of TNF-alpha. The selective ABC1 inhibitors 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and sulfobromophthalein mimicked the suppressive effect of glibenclamide on IL-12 p40 production. On the other hand, both the MDR inhibitor verapamil and CFTR blocker 2,2'-iminodibenzoic acid failed to suppress the production of IL-12 p40. Furthermore, selective inhibitors and activators of SURs were without effect. In agreement with the pharmacological data, macrophages expressed mRNA for ABC1, but not SURs or CFTR. Intracellular levels of IL-12 p40 were decreased by glibenclamide, suggesting that glibenclamide does not affect IL-12 p40 secretion. The effect of glibenclamide did not involve an interference with the activation of the p38 and p42/44 mitogen-activated protein kinases or c-Jun kinase. Glibenclamide also suppressed IFN-gamma-induced up-regulation of major histocompatibility complex II. Taken together, our results indicate that ABC proteins regulate LPS and/or IFN-gamma-induced macrophage activation.
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PMID:Inhibitors of ATP-binding cassette transporters suppress interleukin-12 p40 production and major histocompatibility complex II up-regulation in macrophages. 1190 63

The role of p38- and extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathways in the up-regulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) production in macrophages stimulated with Streptococcus pneumoniae was examined. Inhibitors of p38 kinases effected significant decreases in the accumulation of iNOS protein in macrophages challenged with pneumococcal cell wall preparations or antibiotic-killed pneumococci, even when added up to 6 h after bacterial challenge. In contrast, ERK pathway inhibitors failed to inhibit pneumococcus-induced iNOS protein accumulation. ERK pathway inhibitors significantly reduced TNF secretion when added at the same time as pneumococcal challenge, and inhibitors of both ERK and p38 pathways reduced TNF secretion when added to the macrophages 1 h before stimulation. These data confirm the importance of the p38 and ERK MAP kinase pathways in macrophage activation by bacterial products but indicate that these 2 kinase pathways regulate different macrophage responses in a temporally distinct manner.
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PMID:Differential effects of p38- and extracellular signal-regulated kinase mitogen-activated protein kinase inhibitors on inducible nitric oxide synthase and tumor necrosis factor production in murine macrophages stimulated with Streptococcus pneumoniae. 1192 Mar 16


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