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)

The RON receptor tyrosine kinase is activated by macrophage-stimulating protein, which regulates macrophage migration, phagocytosis, and nitric oxide production. We report here the inhibitory effect of RON on lipopolysaccharide (LPS)-induced cyclooxygenase (Cox)-2 expression in mouse macrophages. In RON-expressing macrophages treated with macrophage stimulating protein, LPS-induced prostaglandin E(2) (PGE(2)) production was significantly reduced. The inhibition was accompanied by reduction of Cox-2 protein and mRNA expression. Transcriptional studies indicated that RON activation inhibits LPS-induced luciferase activity driven by the Cox-2 gene promoter. To determine whether RON activation affects LPS-induced NF-kappa B pathway, which is important for Cox-2 expression. Western blot analyses were performed showing that RON activation inhibits LPS-induced I kappa B alpha degradation. The decreased I kappa B alpha degradation was due to reduced I kappa B alpha phosphorylation at Ser-32 as determined by I kappa B alpha (Ser-32) phosphor-antibody. Moreover, we found that LPS-induced IKK beta activity, an enzyme responsible for phosphorylation of I kappa B alpha, was inhibited upon RON activation. Interestingly, these inhibitory effects were not regulated by RON-mediated phosphatidylinositol-3 kinase. These results suggest that RON activation inhibits LPS-induced macrophage Cox-2 expression. The inhibitory effect is mediated by impairing LPS-activated cascade enzymes that activate NF-kappa B. The inhibition of Cox-2 expression might represent a novel mechanism for the inhibitory functions of RON in vivo against LPS-induced inflammation and septic shock.
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PMID:Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages. 1217 64

In the central nervous system, glial cells play an important role in inflammatory and immune responses, and opioid peptides have been identified as essential mediators between the nervous and the immune systems. We report the profound upregulation of the opioid-related nociceptin/orphanin FQ (N/OFQ) by inflammatory mediators in astrocytes. The bacterial endotoxin, lipopolysaccharide (LPS), and the proinflammatory cytokines, interleukin-beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), induced levels of N/OFQ mRNA and immunoreactivity. HPLC analysis of the immunoreactivity in astrocyte extracts revealed that a large molecular weight precursor for N/OFQ is being synthesized and released in response to LPS and astrocytes appear to lack the enzymes required to process the precursor protein. Western blot analysis showed that LPS treatment elicited the activation of ERK 1/2 and p38 MAP kinases. Blockade of the p38 or the ERK MAP kinase pathways prevented the LPS-induced increase in N/OFQ mRNA levels indicating a role for these cascades in the regulation of N/OFQ genes in response to LPS. Regulation of N/OFQ gene expression by ERK and p38 activation may be mediated through the transcription factor CREB. We observed CREB phosphorylation in response to LPS, which was also prevented by SB202190 and PD98059. The NFkappaB pathway also appears to be involved in the induction of N/OFQ transcription by LPS, since NFkappaB inhibitors antagonized the effect of LPS on N/OFQ expression. Regulation of N/OFQ by inflammatory mediators in astrocytes may suggest a role for N/OFQ in neural-glial communication and in inflammatory responses in certain neuropathophysiological conditions.
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PMID:Inflammatory mediators increase the expression of nociceptin/orphanin FQ in rat astrocytes in culture. 1220 90

Macrophage activation by bacterial lipopolysaccharide (LPS) promotes the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and of secondary mediators, such as leukotrienes and prostaglandins (PGs). Mice lacking the gene encoding the serine/threonine protein kinase Tpl2/Cot produce low levels of TNF-alpha in response to LPS because of an ERK-dependent post-transcriptional defect, and they are resistant to LPS/D-galactosamine-induced endotoxin shock. In this study we demonstrate that prostaglandin E2 and its regulatory enzyme, COX-2, are also targets of Tpl2-transduced LPS signals in bone marrow-derived mouse macrophages. Thus, LPS-stimulated Tpl2(-/-) macrophages express low levels of COX-2 and PGE2, compared with wild-type Tpl2(+/+) cells. The ability of Tpl2 to regulate COX-2 expression depends on ERK signals that activate p90Rsk and Msk1, which in turn phosphorylate CREB, a key regulator of COX-2 transcription. These data identify physiological targets of Tpl2 signaling downstream of ERK and further implicate Tpl2 in the pathophysiology of inflammation.
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PMID:Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. 1223 23

One of the immediate early microglial genes that are up-regulated in response to proinflammatory stimuli is cyclo-oxygenase 2 (COX-2). In the present study, we have investigated the effects of alpha-tocopherol (alpha TocH), an essential constituent of the nervous system, on the activation of COX-2 in lipopolysaccharide (LPS)-stimulated mouse BV-2 microglia. In unstimulated BV-2 cells, COX-2 mRNA and protein were almost undetectable but were strongly up-regulated in response to LPS. Activation of COX-2 protein synthesis in LPS-stimulated BV-2 cells involved activation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathway and was sensitive to the protein kinase C (PKC) inhibitors staurosporine and chelerythrine, and the MAP kinase/ERK kinase 1/2 inhibitors PD98059 and U0126. Supplementation of BV-2 cells with alpha TocH before LPS stimulation resulted in pronounced up-regulation of protein phosphatase 2A (PP2A) activity, down-regulation of PKC activity, ERK1/2 phosphorylation and nuclear factor kappa B (NF kappa B) activation. As a result, COX-2 protein levels and prostaglandin E(2) production were significantly lower in alpha TocH-supplemented cells. The effects of alpha TocH on PKC activity could be reverted by calyculin A and okadaic acid, two PP inhibitors. In summary, our results suggest that alpha TocH activates microglial PP2A activity and thereby silences an LPS-activated PKC/ERK/NF kappa B signalling cascade resulting in significantly attenuated COX-2 protein synthesis. These in vitro results imply that alpha TocH could induce quiescence to pathways that are associated with acute or chronic inflammatory conditions in the central nervous system.
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PMID:Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and synthesis in immortalized murine BV-2 microglia. 1242 20

Secreted proteins of Mycobacterium tuberculosis are major targets of the specific immunity in tuberculosis and constitute promising candidates for the development of more efficient vaccines and diagnostic tests. We show here that M. tuberculosis-specific antigen 10 (MTSA-10, originally designated CFP-10) can bind to the surface of mouse J774 macrophage-like cells and stimulate the secretion of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). MTSA-10 also synergized with gamma interferon (IFN-gamma) for the induction of the microbicidal free radical nitric oxide (NO) in J774 cells, as well as in bone marrow-derived and peritoneal macrophages. On the other hand, pretreatment of J774 cells with MTSA-10 markedly reduced NO but not TNF-alpha or interleukin 10 (IL-10) release upon subsequent stimulation with lipopolysaccharide or the cell lysate of M. tuberculosis. The presence of IFN-gamma during stimulation with M. tuberculosis lysate antagonized the desensitizing effect of MTSA-10 pretreatment on macrophage NO production. The activation of protein tyrosine kinases (PTK) and the serine/threonine kinases p38 MAPK and ERK was apparently required for MTSA-10 induction of TNF-alpha and NO release, as revealed by specific kinase inhibitors. However, only p38 MAPK activity, not PTK or ERK activity, was partly responsible for MTSA-10-mediated macrophage desensitization. The modulation of macrophage function by MTSA-10 suggests a novel mechanism for its involvement in immunopathogenesis of tuberculosis and might have implications for the prevention, diagnosis, and therapy of this disease.
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PMID:Effect of Mycobacterium tuberculosis-specific 10-kilodalton antigen on macrophage release of tumor necrosis factor alpha and nitric oxide. 1243 25

The intracellular, gram-negative pathogen Brucella abortus establishes chronic infections in host macrophages while downregulating cytokines such as tumor necrosis factor alpha (TNF-alpha). When producing TNF-alpha, Brucella abortus rough lipopolysaccharide (LPS) activates the same mitogen-activated protein kinase signaling pathways (ERK and JNK) as Escherichia coli LPS, but Brucella LPS is a much less potent agonist.
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PMID:Rough lipopolysaccharide from Brucella abortus and Escherichia coli differentially activates the same mitogen-activated protein kinase signaling pathways for tumor necrosis factor alpha in RAW 264.7 macrophage-like cells. 1243 3

mRNA stabilization plays an important role in the changes in protein expression initiated by inducers of inflammation or direct cell stress such as UV light. This study provides evidence that stabilization in response to UV light differs from that induced by proinflammatory stimuli such as bacterial lipopolysaccharide or interleukin (IL)-1. Firstly, UV-induced stabilization is independent of the p38 MAP kinase pathway, which has previously been shown to mediate stabilization induced by IL-1 or lipopolysaccharide. UV-induced mRNA stabilization was insensitive to the dominant negative forms of p38 MAP kinase and its substrate MAP kinase-activated protein kinase 2 (MK2), or to the p38 MAP kinase inhibitor SB 203580, demonstrating that it occurs through a different signaling mechanism. Secondly, UV-induced stabilization exhibits a different transcript selectivity. Activation of the p38 MAP kinase pathway, by expressing active MAP kinase kinase 6, induced stabilization only of transcripts containing AU-rich elements. UV light also induced stabilization of transcripts lacking AU-rich elements. This effect could not be mimicked by expressing MEKK1, an upstream activator of the p38, JNK, ERK and NF-kappaB pathways. UV light also stabilized endogenous histone mRNA, which lacks AU-rich elements and a poly(A) tail. This effect was not mimicked by active MAP kinase kinase 6 and not sensitive to a p38 MAP kinase inhibitor. This suggests that UV light induces stabilization through a mechanism that is independent of p38 MAP kinase and affects a broad spectrum of mRNAs.
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PMID:Evidence for general stabilization of mRNAs in response to UV light. 1244 71

Macrophage-stimulating protein (MSP) is a serum protein belonging to the plasminogen-related growth factor family. The specific receptor for MSP is the RON (recepteur d'origine nantais) receptor tyrosine kinase - a member of the MET proto-oncogene family. Activation of RON by MSP exerts dual functions on macrophages. The stimulatory activities include the induction of macrophage spreading, migration and phagocytosis. However, MSP also inhibits lipopolysaccharide (LPS)-induced production of inflammatory mediators, including inducible nitric oxide and prostaglandins. These suppressive effects are mediated by RON-transduced signals that block LPS-induced enzymatic cascades that activate nuclear factor kappa-B (NFkappaB) pathways. Recent in vivo studies demonstrated that inactivation of the RON gene results in increased inflammatory responses and susceptibility to LPS-induced septic death in mice, suggesting that RON expression is required for attenuating the extent of inflammatory responses in vivo. Thus, MSP and RON are potential regulators that control macrophage activities during bacterial infection in vivo.
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PMID:Macrophage-stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities. 1247 65

CD14 is the primary receptor for lipopolysaccharide (LPS)that plays important roles in host defense and subserves other host-related biological functions. We previously identified CD14 on cultured human retinal pigment epithelial (HRPE) cells using immunocytochemical techniques. In this study, we investigated immunoreactive HRPE CD14 expression by immunohistochemically staining HRPE cells and HRPE cells in sections of human eyes with anti-CD14 monoclonal antibodies (mAb). Constitutive HRPE gene and protein expression were confirmed by semiquantitative PCR and western blotting. ELISA for cell-associated and secreted (s) HRPE CD14 revealed that specific digestion by phosphoinositol-specific phospholipase C (PI-PLC) significantly reduced (P<0.01) cell-associated HRPE CD14 which was not modulated by LPS or gamma-IFN. ELISA of the conditioned media (CM) of HRPE cells treated with PI-PLC contained significantly more (P<0.001) sCD14, but sCD14 was not modulated by LPS or gamma-IFN. FACS analysis confirmed HRPE cell surface CD14. To show functional CD14, fluorescently-labelled LPS and CD14 were demonstrated to show significant co-localization on live, cultured HRPE cells in close proximity (<7A) as demonstrated by resonance energy transfer of the fluorescent ligands (P<0.0001). Significant inhibition (P<0.001) of LPS-induced IL-8 secretion, as measured by ELISA, occurred in the presence of function blocking anti-CD14 mAb. Significant inhibition of LPS-induced HRPE IL-8 secretion by PKC, PTK, PI3 kinase, and p38 kinase inhibitors indicated cell mediators responsible for LPS-induced HRPE chemokine secretion. This study demonstrates that HRPE cells express functional CD14 in vitro and in situ along at the outer blood-retina barrier.
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PMID:RPE CD14 immunohistochemical, genetic, and functional expression. 1257 61

Mitogen-activated protein kinases (MAPKs) are part of an intracellular signaling machinery consisting of three known distinct pathways, each leading to activation of a different protein kinase: p38, ERK (extracellular signal-regulated kinase), or JNK (c-Jun N-terminal kinase). We investigated the role of the p38 MAPK pathway in the phenomenon of lung endotoxin "priming": incubation of perfused rat lungs with lipopolysaccharide (LPS) for 2 hours results in drastically enhanced cyclooxygenase-2-dependent and thromboxane synthase-dependent vasoconstriction and bronchoconstriction, including edema formation in response to a second inflammatory stimulus, such as arachidonic acid application. Two unrelated selective inhibitors of p38 (SB203580 and SC-68376) dose dependently suppressed the arachidonic acid-induced pulmonary artery pressor response, edema formation, and bronchoconstrictor response in both control lungs and lungs that underwent preceding endotoxin priming. In parallel, thromboxane, but not prostacyclin, released into the lung perfusate was dose dependently inhibited. Using immunohistochemical techniques in combination with quantitative microdensitometry, p38 was detected in nearly all cell types in control lungs, whereas the activated form p-p38 was only expressed in certain cell types, eg, bronchial epithelial cells, endothelial cells, alveolar macrophages, and vascular smooth muscle cells (SMC) of small vessels. In response to endotoxin, p-p38 expression was additionally observed in septal cells, bronchial SMC, and vascular SMC of larger pulmonary vessels and was increased in most other cell types including small-vessel SMC. We conclude that both immunolocalization of p38 activity and pharmacologic interventions support a strong role of the p38 MAPK pathway in establishing an active cyclooxygenase-2/thromboxane synthase axis in vascular and bronchial SMC, with up-regulation of this signaling cascade occurring in LPS priming and being responsible for enhanced pulmonary artery pressor response, edema formation, and bronchoconstriction. Moreover, LPS induces or increases phosphorylation of p38 in other lung cell types. The physiologic consequences of these events remain to be established.
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PMID:Cyclooxygenase-2-dependent and thromboxane-dependent vascular and bronchial responses are regulated via p38 mitogen-activated protein kinase in control and endotoxin-primed rat lungs. 1264 34


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