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)

The nuclear factor-kappaB (NF-kappaB) pathway is crucial for the survival of B cells stimulated through Toll-like receptors (TLRs). Here, we show that the heightened death of TLR4-activated nfkb1(-/-) B cells is the result of a failure of the Tpl(2)/MEK/ERK pathway to phosphorylate the proapo-ptotic BH3-only protein Bim and target it for degradation. ERK inactivation of Bim after TLR4 stimulation is accompanied by an increase in A1/Bim and Bcl-x(L)/Bim complexes that we propose represents a c-Rel-dependent mechanism for neutralizing Bim. Together these findings establish that optimal survival of TLR4-activated B cells depends on the NF-kappaB pathway neutralizing Bim through a combination of Bcl-2 prosurvival protein induction and Tpl2/ERK-dependent Bim phosphorylation and degradation.
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PMID:NF-kappaB1 and c-Rel cooperate to promote the survival of TLR4-activated B cells by neutralizing Bim via distinct mechanisms. 1880 64

Bacterial endotoxin/lipopolysaccharide elicits inflammatory responses and also elevates circulating levels of free fatty acids (FFAs) and impairs insulin sensitivity. Serum FFA elevation in acute endotoxemia has long been thought to be due to endotoxin dysregulating lipid disposal and counterregulatory hormones and cytokines. Here, we investigated the direct lipolysis effect of endotoxin in rodents and in isolated primary adipocytes. Endotoxin increases lipolysis in vivo in adipose tissues, elevates circulating FFA level, induces insulin resistance in rats, and directly stimulates chronic lipolysis in vitro in adipocytes. The lipolytic action of endotoxin is mediated via its lipid A moiety and is blocked by anti-endotoxin peptides. Neither adipocytokine secretion nor nuclear factor-kappaB activation is involved in endotoxin-induced lipolysis. Different from catecholamine, endotoxin stimulates lipolysis without elevating cAMP production and activating protein kinase A and protein kinase C. Instead, endotoxin induces phosphorylation of Raf-1, MEK1/2, and ERK1/2. Upon inhibition of ERK1/2 but not JNK and p38 MAPK, endotoxin-stimulated lipolysis ceases. Endotoxin causes perilipin down-regulation and phosphorylation and increases the activity and protein levels of hormone-sensitive lipase and adipose triglyceride lipase but does not induce hormone-sensitive lipase translocation to intracellular lipid droplets. In TLR4 (Toll-like receptor 4)-deficient mice and adipocytes, endotoxin fails to increase in vivo and in vitro lipolysis. These findings suggest that endotoxin stimulates lipolysis via TLR4 and ERK1/2 signaling in adipocytes. The lipolytic action of endotoxin liberates FFA efflux from adipocytes to the bloodstream, which is a possible basis for systemic FFA elevation and insulin resistance in endotoxemia or Gram-negative bacterial infection.
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PMID:Bacterial endotoxin stimulates adipose lipolysis via toll-like receptor 4 and extracellular signal-regulated kinase pathway. 1912 98

Toll-like receptor (TLR)4 recognizes microbial pathogens, such as lipopolysaccharide, and mediates lipopolysaccharide-induced proinflammatory cytokine secretion, as well as microbial uptake by macrophages. In addition to exogenous pathogens, TLR4 recognizes modified self, such as minimally oxidized low-density lipoprotein (mmLDL). Here we report that mmLDL and its active components, cholesteryl ester hydroperoxides, induce TLR4-dependent fluid phase uptake typical of macropinocytosis. We show that mmLDL induced recruitment of spleen tyrosine kinase (Syk) to a TLR4 signaling complex, TLR4 phosphorylation, activation of a Vav1-Ras-Raf-MEK-ERK1/2 signaling cascade, phosphorylation of paxillin, and activation of Rac, Cdc42, and Rho. These mmLDL-induced and TLR4- and Syk-dependent signaling events and cytoskeletal rearrangements lead to enhanced uptake of small molecules, dextran, and, most importantly, both native and oxidized LDL, resulting in intracellular lipid accumulation. An intravenous injection of fluorescently labeled mmLDL in wild-type mice resulted in its rapid accumulation in circulating monocytes, which was significantly attenuated in TLR4-deficient mice. These data describe a novel mechanism leading to enhanced lipoprotein uptake in macrophages that would contribute to foam cell formation and atherosclerosis. These data also suggest that cholesteryl ester hydroperoxides are an endogenous ligand for TLR4. Because TLR4 is highly expressed on the surface of circulating monocytes in patients with chronic inflammatory conditions, and cholesteryl ester hydroperoxides are present in plasma, lipid uptake by monocytes in circulation may contribute to the pathological roles of monocytes in chronic inflammatory diseases.
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PMID:Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake. 1946 Oct 45

Ketamine may affect the host immunity. Interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) are pivotal cytokines produced by macrophages. This study aimed to evaluate the effects of ketamine on the regulation of inflammatory cytokine gene expression, especially IL-1 beta, in lipopolysaccharide (LPS)-activated murine macrophage-like Raw 264.7 cells and its possible signal-transducing mechanisms. Administration of Raw 264.7 cells with a therapeutic concentration of ketamine (100 microM), LPS, or a combination of ketamine and LPS for 1, 6, and 24 h was not cytotoxic to macrophages. Exposure to 100 microM ketamine decreased the binding affinity of LPS and LPS-binding protein but did not affect LPS-induced RNA and protein synthesis of TLR4. Treatment with LPS significantly increased IL-1 beta, IL-6, and TNF-alpha gene expressions in Raw 264.7 cells. Ketamine at a clinically relevant concentration did not affect the synthesis of these inflammatory cytokines, but significantly decreased LPS-caused increases in these cytokines. Immunoblot analyses, an electrophoretic mobility shift assay, and a reporter luciferase activity assay revealed that ketamine significantly decreased LPS-induced translocation and DNA binding activity of nuclear factor-kappa B (NF kappaB). Administration of LPS sequentially increased the phosphorylations of Ras, Raf, MEK1/2, ERK1/2, and IKK. However, a therapeutic concentration of ketamine alleviated such augmentations. Application of toll-like receptor 4 (TLR4) small interfering (si)RNA reduced cellular TLR4 amounts and ameliorated LPS-induced RAS activation and IL-1 beta synthesis. Co-treatment with ketamine and TLR4 siRNA synergistically ameliorated LPS-caused enhancement of IL-1 beta production. Results of this study show that a therapeutic concentration of ketamine can inhibit gene expression of IL-1 beta possibly through suppressing TLR4-mediated signal-transducing phosphorylations of Ras, Raf, MEK1/2, ERK1/2, and IKK and subsequent translocation and transactivation of NF kappaB.
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PMID:Signal-transducing mechanisms of ketamine-caused inhibition of interleukin-1 beta gene expression in lipopolysaccharide-stimulated murine macrophage-like Raw 264.7 cells. 1954 Aug 66

Bacterial infection of the kidney is associated with renal tubule dysfunction and dysregulation of systemic electrolyte balance. Whether bacterial molecules directly affect renal tubule transport is unknown. We examined the effects of LPS on HCO3(-) absorption in the isolated rat and mouse medullary thick ascending limb (MTAL). LPS decreased HCO3(-) absorption when added to bath or lumen. The MEK/ERK inhibitor U0126 eliminated inhibition by bath LPS but had no effect on inhibition by lumen LPS. Conversely, the mammalian target of rapamycin (mTOR) inhibitor rapamycin eliminated inhibition by lumen LPS but had no effect on inhibition by bath LPS. Inhibiting basolateral Na(+)/H(+) exchange with amiloride eliminated inhibition of HCO3(-) absorption by lumen but not bath LPS. Confocal immunofluorescence showed expression of TLR4 in basolateral and apical membrane domains. Inhibition of HCO3(-) absorption by bath and lumen LPS was eliminated in MTALs from TLR4(-/-) mice. Thus LPS inhibits HCO3(-) absorption through distinct TLR4-dependent pathways in basolateral and apical membranes. These results establish that bacterial molecules can directly impair the transport function of renal tubules, identifying a new mechanism contributing to tubule dysfunction during bacterial infection. The LPS-induced reduction in luminal acidification may contribute to Gram-negative pathogenicity by promoting bacterial adherence and growth and impairing correction of infection-induced systemic acid-base disorders.
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PMID:Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes. 1967 79

Helicobacter pylori is recognized as an etiological agent of gastroduodenal diseases. H. pylori produces various toxic substances, including lipopolysaccharide (LPS). However, H. pylori LPS exhibits extremely weakly endotoxic activity compared to the typical LPS, such as that produced by Escherichia coli, which acts through Toll-like receptor 4 (TLR4) to induce inflammatory molecules. The gastric epithelial cell lines MKN28 and MKN45 express TLR4 at very low levels, so they show very weak interleukin-8 (IL-8) production in response to E. coli LPS, but pretreatment with H. pylori LPS markedly enhanced IL-8 production induced by E. coli LPS by upregulating TLR4 via TLR2 and the MEK1/2-ERK1/2 pathway. The transcription factor NF-Y was activated by this signal and promoted transcription of the tlr4 gene. These MEK1/2-ERK1/2 signal-mediated activities were more potently activated by LPS carrying a weakly antigenic epitope, which is frequently found in gastric cancers, than by LPS carrying a highly antigenic epitope, which is associated with chronic gastritis. H. pylori LPS also augmented the proliferation rate of gastric epithelial cells via the MEK1/2-ERK1/2 pathway. H. pylori LPS may be a pathogenic factor causing gastric tumors by enhancing cell proliferation and inflammation via the MEK1/2-ERK1/2 mitogen-activated protein kinase cascade in gastric epithelial cells.
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PMID:Helicobacter pylori lipopolysaccharides upregulate toll-like receptor 4 expression and proliferation of gastric epithelial cells via the MEK1/2-ERK1/2 mitogen-activated protein kinase pathway. 1985 8

Exposure to cigarette smoke extract (CSE) leads to airway and lung inflammation through an oxidant-antioxidant imbalance. Cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) have been shown to play critical roles in respiratory inflammation. Here, we show that COX-2/PGE(2)/IL-6 induction is dependent on Toll-like receptor 4 (TLR4)/NADPH oxidase signaling in human tracheal smooth muscle cells (HTSMCs). CSE induced COX-2 expression in vitro in HTSMCs and in vivo in the airways of mice. CSE also directly caused an increase in TLR4. Moreover, CSE-regulated COX-2, PGE(2), and IL-6 generation was inhibited by pretreatment with TLR4 Ab; inhibitors of c-Src (PP1), NADPH oxidase (diphenylene iodonium chloride and apocynin), p38 MAPK (SB202190), MEK1/2 (U0126), JNK1/2 (SP600125), and NF-kappaB (helenalin); a ROS scavenger (N-acetyl-l-cysteine); and transfection with siRNA of TLR4, MyD88, TRAF6, Src, p47(phox), p38, p42, JNK2, or p65. CSE-induced leukocyte numbers in BAL fluid were also reduced by pretreatment with these inhibitors. Furthermore, CSE induced p47(phox) translocation and TLR4/MyD88/TRAF6 and c-Src/p47(phox) complex formation. We found that PGE(2) enhanced IL-6 production in HTSMCs and leukocyte count in BAL fluid. In addition, treatment with nicotine could induce COX-2, PGE(2), and IL-6 generation in in vivo and in vitro studies. These results demonstrate that CSE-induced ROS generation was mediated through the TLR4/MyD88/TRAF6/c-Src/NADPH oxidase pathway, in turn initiated the activation of MAPKs and NF-kappaB, and ultimately induced COX-2/PGE(2)/IL-6-dependent airway inflammation.
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PMID:Induction of COX-2/PGE(2)/IL-6 is crucial for cigarette smoke extract-induced airway inflammation: Role of TLR4-dependent NADPH oxidase activation. 1989 12

Guanine-nucleotide exchange factors (GEFs) stimulate the intrinsic GDP/GTP exchange activity of Ras and promote the formation of active Ras-GTP, which in turn controls diverse signalling networks important for the regulation of cell proliferation, survival, differentiation, vesicular trafficking, and gene expression. RasGEF1b is a GEF, whose expression is induced in macrophages on stimulation with toll-like receptor (TLR) agonists. Here, we showed that in vitro RasGEF1b expression by macrophages is mostly induced by TLR3 (poly I:C) and TLR4 (lipopolysaccharyde) through the MyD88-independent pathway. In vivo infection with the protozoan parasites Trypanosoma cruzi and Plasmodium chabaudi induced RasGEF1b in an MyD88-, TRIF-, and IFN-gamma-dependent manner. Ectopically expressed RasGEF1b was found, mostly, in the heavy membrane fraction of HEK 293T, and by confocal microscopy, it was found to be located at early endosomes. Computational modelling of the RasGEF1b-Ras interaction revealed that RasGEF1b interacts with the binding domain site of Ras, a critical region for interacting with GEFs involved in the activation of Ras-Raf-MEK-ERK pathway. More important, RasGEF1b was found to be closely associated with Ras in live cells and to trigger Ras activity. Altogether, these results indicate that on TLR activation, RasGEF1b may trigger Ras-like proteins and regulate specific biological activities described for this subtype of GTPases.
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PMID:Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor. 2009 Jul 72

Lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4)-mediated signaling pathways have caught the attention of strategies designed for rheumatoid arthritis (RA). In this study, we identified that cPLA(2)alpha acted as a modulator of LPS-induced VCAM-1 expression and THP-1 (human acute monocytic leukemia cell line) adherence. Treatment of RA synovial fibroblasts (RASFs) with LPS, a TLR4 agonist, promoted the VCAM-1 expression and THP-1 adherence which were decreased by pretreatment with a selective cytosolic phospholipase A(2) (cPLA(2)) inhibitor (AACOCF(3)), implying the involvement of cPLA(2)alpha in these responses. This notion was further confirmed by knockdown of cPLA(2)alpha expression by transfection with cPLA(2)alpha small interfering RNA (siRNA) leading to a decrease in VCAM-1 expression and THP-1 adherence induced by LPS. Subsequently, the LPS-stimulated cPLA(2)alpha phosphorylation was attenuated by pretreatment with a MEK1/2 inhibitor (U0126), suggesting that LPS-stimulated cPLA(2)alpha phosphorylation and activity are mediated through an ERK-dependent mechanism. Moreover, COX-2-derived PGE(2) production appeared to involve in LPS-induced VCAM-1 expression which was attenuated by pretreatment with selective COX-2 inhibitors (NS-398 and celecoxib), transfection with COX-2 siRNA, or PGE(2) receptor antagonists. In addition, pretreatment with ecosapentaenoic acid (EPA), a substrate competitor of arachidonic acid (AA), also blocked LPS-induced VCAM-1 mRNA and protein expression, and THP-1 adherence. Collectively, these results suggest that LPS-induced VCAM-1 expression and adhesion of THP-1 cells are mediated through the TLR4/ERK/cPLA(2)alpha phosphorylation and COX-2 expression/PGE(2) synthesis in RASFs.
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PMID:TLR4-dependent induction of vascular adhesion molecule-1 in rheumatoid arthritis synovial fibroblasts: Roles of cytosolic phospholipase A(2)alpha/cyclooxygenase-2. 2011 84

Bacterial infection and sepsis are associated with renal tubule dysfunction and dysregulation of systemic electrolyte balance but the underlying mechanisms are incompletely understood. Recently, we demonstrated that HCO(3)(-) absorption by the medullary thick ascending limb (MTAL) is inhibited by gram-negative bacterial LPS through activation of Toll-like receptor 4 (TLR4). Here, we examined whether MTAL transport is altered by activation of TLR2, the receptor predominantly responsible for recognizing gram-positive bacteria. Confocal immunofluorescence showed expression of TLR2 in the basolateral membrane domain of rat and mouse MTALs. The functional role of TLR2 was examined in perfused MTALs using Pam(3)CSK(4), a bacterial lipoprotein analog that specifically activates TLR2. Adding Pam(3)CSK(4) to the bath decreased HCO(3)(-) absorption by 25%. The inhibition by Pam(3)CSK(4) was eliminated in MTALs from TLR2(-/-) mice. HCO(3)(-) absorption was also inhibited by the TLR2 agonists lipoteichoic acid and peptidoglycan, two cell wall components of gram-positive bacteria. The MEK/ERK inhibitor U0126 eliminated inhibition of HCO(3)(-) absorption by bath LPS but had no effect on inhibition by Pam(3)CSK(4). The inhibition by Pam(3)CSK(4) was eliminated by the protein kinase C inhibitors chelerythrine Cl and bisindolylmaleimide. Moreover, the inhibition by Pam(3)CSK(4), lipoteichoic acid, and peptidoglycan was additive to inhibition by LPS. Thus, agonists of basolateral TLR2 and TLR4 inhibit HCO(3)(-) absorption independently through distinct signaling pathways. We conclude that bacterial components act directly through TLRs to modify the transport function of renal tubules. During polymicrobial sepsis, gram-positive bacterial molecules acting through TLR2 and gram-negative LPS acting through TLR4 can function through parallel signaling pathways to impair MTAL transport. The inhibition of luminal acidification may impair the ability of the kidneys to correct systemic acidosis that contributes to sepsis pathogenesis.
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PMID:Toll-like receptor 2 mediates inhibition of HCO(3)(-) absorption by bacterial lipoprotein in medullary thick ascending limb. 2055 44


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