EC:2.7.11.24 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of cyclooxygenase-2 (COX-2) and the synthesis of prostaglandin E2 (PGE2) as well as of cytokines such as interleukin-6 (IL-6) have all been suggested to propagate neuropathology in different brain disorders such as HIV-dementia, prion diseases, stroke and Alzheimer's disease. In this report, we show that PGE2-stimulated IL-6 release in U373 MG human astroglioma cells and primary rat astrocytes. PGE2-induced intracellular cAMP formation was mediated via prostaglandin E receptor 2 (EP2), but inhibition of cAMP formation and protein kinase A or blockade of EP1/EP2 receptors did not affect PGE2-induced IL-6 synthesis. This indicates that the cAMP pathway is not part of PGE2-induced signal transduction cascade leading to IL-6 release. The EP3/EP1-receptor agonist sulprostone failed to induce IL-6 release, suggesting an involvement of EP4-like receptors. PGE2-activated p38 mitogen-activated kinase (p38 MAPK) and protein kinase C (PKC). PGE2-induced IL-6 synthesis was inhibited by specific inhibitors of p38 MAPK (SB202190) and PKC (GF203190X). Although, up to now, EP receptors have only rarely been linked to p38 MAPK or PKC activation, these results suggest that PGE2 induces IL-6 via an EP4-like receptor by the activation of PKC and p38 MAPK via an EP4-like receptor independently of cAMP.
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PMID:Mechanisms of prostaglandin E2-induced interleukin-6 release in astrocytes: possible involvement of EP4-like receptors, p38 mitogen-activated protein kinase and protein kinase C. 1173 6

Bradykinin induced prostaglandin E(2) release from the Swiss 3T3 fibroblasts, preconditioned with fresh culture medium. Although treatment with genistein for the entire period of preconditioning and incubation with bradykinin attenuated prostaglandin E(2) release, treatment with fresh culture medium and genistein for only the preconditioning period further augmented the prostaglandin E(2) release. In the cells preconditioned with fresh culture medium and genistein, bradykinin caused the phosphorylation of protein tyrosine and mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK), followed by arachidonic acid release. Interestingly, preconditioning with genistein alone also caused phosphorylation and arachidonic acid release, probably reflecting rebound activation after the washout of genistein. However, preconditioning with genistein alone induced neither the augmentation of prostaglandin E(2) release nor the expression of cyclooxygenase-2. The further potentiation of bradykinin-induced prostaglandin E(2) release by combined preconditioning with fresh culture medium and genistein may be due to the activation of the MAPK/ERK-c phospholipase A(2) pathway by preconditioning with genistein.
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PMID:Preconditioning of 3T3 cells by fresh medium together with genistein enhances prostaglandin E(2) release. 1174 Sep 48

This study investigated the actions of fibroblast growth factor (FGF)-18, a novel member of the FGF family, on osteoblasts, chondrocytes, and osteoclasts and compared them with those of FGF-2 and FGF-10. FGF-18 stimulated the proliferation of cultured mouse primary osteoblasts, osteoblastic MC3T3-E1 cells, primary chondrocytes, and prechondrocytic ATDC5 cells, although it inhibited the differentiation and matrix synthesis of these cells. FGF-18 up-regulated the phosphorylation of extracellular signal-regulated kinase in both osteoblasts and chondrocytes and up-regulated the phosphorylation of p38 mitogen-activated protein kinase only in chondrocytes. FGF-18 mitogenic actions were blocked by a specific inhibitor of extracellular signal-regulated kinase in both osteoblasts and chondrocytes and by a specific inhibitor of p38 mitogen-activated protein kinase in chondrocytes. With regard to the action of FGF-18 on bone resorption, FGF-18 not only induced osteoclast formation through receptor activator of nuclear factor-kappaB ligand and cyclooxygenase-2 but also stimulated osteoclast function to form resorbed pits on a dentine slice in the mouse coculture system. All these effects of FGF-18 bore a close resemblance to those of FGF-2, whereas FGF-10 affects none of these cells. FGF-18 may therefore compensate for the action of FGF-2 on bone and cartilage.
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PMID:Regulation of osteoblast, chondrocyte, and osteoclast functions by fibroblast growth factor (FGF)-18 in comparison with FGF-2 and FGF-10. 1174 78

Endotoxin tolerance was initially described when it was observed that animals survived a lethal dose of bacterial endotoxin if they had been previously treated with a sublethal injection. In animal models, two phases of endotoxin tolerance are described, an early phase associated with altered cellular activation and a late phase associated with the development of specific antibodies against the polysaccharide side chain of Gram-negative organisms. Recently, there has been a tremendous resurgence of interest in the mechanisms responsible for altered responsiveness to bacterial endotoxin. Host immune cells, particularly macrophages and monocytes, that are exposed to endotoxin for 3 to 24 hrs are rendered "tolerant" and manifest a profoundly altered response when rechallenged with bacterial endotoxin or lipopolysaccharide. The "lipopolysaccharide-tolerant" phenotype is characterized by inhibition of lipopolysaccharide-stimulated tumor necrosis factor production, altered interleukin-1 and interleukin-6 release, enhanced cyclooxygenase-2 activation, inhibition of mitogen-activated protein kinase activation, and impaired nuclear factor-kappa B translocation. Human monocytes and macrophages can be induced to become tolerant, and there is increasing evidence that monocytic cells from patients with systemic inflammatory response syndrome and sepsis have many characteristics of endotoxin tolerance.
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PMID:Endotoxin tolerance: a review. 1178 63

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

Myocardial infarction is followed by a complex repair process that includes a significant role for inflammatory cells. Cyclooxygenase-2 (COX-2) plays a key role in mediating inflammation. Contribution of COX-2 to inflammatory response following myocardial infarction is less certain. In an effort to evaluate the function of COX-2 and prostaglandin E(2)(PGE(2)) in myocardial infarction, we examined the role of COX-2 after angiotensin II (Ang II) stimulation in cardiac fibroblasts and in rats with experimental myocardial infarction (MI). We combined Western blot analysis and enzyme immunoassay to demonstrate COX-2 expression and PGE(2)release in cardiac fibroblasts. Isolated cardiac fibroblasts were stimulated with Ang II. Unstimulated fibroblasts showed no COX-2 protein expression. Fibroblasts stimulated with Ang II showed a strong time-dependent expression of COX-2 protein. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 but not the p42/44 MAPK-inhibitor PD98059 suppressed Ang II-induced COX-2 protein expression. COX-2 expression correlated with a significantly increased PGE(2)release from cardiac fibroblasts. The COX-2 specific inhibitor NS-398 suppressed the Ang II-stimulated PGE(2)production. We then investigated COX-2 expression and inflammatory cell infiltration in our rat model of myocardial infarction. MI was produced by coronary artery ligation in adult female Wistar rats. The period of coronary artery occlusion was 96 h. The selective COX-2 inhibitor rofecoxib (3 mg/kg/d), administered orally, was given one day before MI and continued for four days. Western blotting showed expression of COX-2 protein in the area of necrosis and the infarct border zone. Immunofluorescence analysis showed macrophage infiltration as well as fibroblast proliferation in the infarct border zone of 4-d infarcted tissue and a significantly reduced cell invasion and fibroblast proliferation in infarcted tissue of rats treated with rofecoxib. MI size at day 4 was comparable in untreated and treated rats. In conclusion, we demonstrate that pharmacological interference with prostaglandin synthesis in myocardial infarction is associated with reduced myocardial invasion of inflammatory cells.
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PMID:Cyclooxygenase-2 in myocardium stimulation by angiotensin-II in cultured cardiac fibroblasts and role at acute myocardial infarction. 1181 59

Prostaglandins (PGs) are known to play a key role in the initiation of labor, but the mechanisms regulating their synthesis in amnion are largely unknown. In this study, the regulatory mechanisms for PGE(2) production during phospholipase D (PLD) and p38-dependent activation of WISH cells were investigated. We found that the stimulation of WISH cells with interleukin (IL)-1 beta elicited dose-dependent synthesis of cyclooxygenase-2 (COX-2) mRNA, protein, and their products, PGE(2). Moreover, the treatment of [(3)H]myristate-labeled cells in the presence of 1-butanol caused the dose-dependent formation of [(3)H]phosphatidylbutanol (PBt), a product specific to PLD activity. Pretreating the cells with 1-butanol and Ro 31-8220 inhibited the IL-1 beta-induced COX-2 expression, but 3-butanol did not affect this response. In addition, evidence that PLD was involved in the stimulation of COX-2 expression was provided by the observations that COX-2 expression was stimulated by the dioctanoyl phosphatidic acid (PA) and that the prevention of PA dephosphorylation by 1-propranolol potentiated COX-2 expression by IL-1 beta. Moreover, IL-1 beta stimulation of the cells caused the phosphorylation of p38 and extracellular signal-regulated kinase (ERK), and IL-1 beta-induced COX-2 expression was inhibited by the pretreatment of WISH cells with a p38 inhibitor, in contrast ERK upstream inhibitor had no effect. Furthermore, Ro 31-8220 inhibited IL-1 beta-induced p38 phosphorylation but not ERK phosphorylation. The results of this study indicate that in human amnion cells, IL-1 beta might activate PLD through an upstream protein kinase C to elicit p38 and finally induce COX-2 expression.
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PMID:Regulation of cyclooxygenase-2 expression by phospholipase D in human amnion-derived WISH cells. 1185 42

Elevated mucosal interleukin-1 (IL-1) levels are frequently seen during acute and chronic intestinal inflammation, and IL-1 neutralization lessens the severity of inflammation. One major effect of IL-1 is the increased release of eicosanoid mediators via induction of cyclooxygenase-2 (COX-2). One site of COX-2-derived prostaglandin synthesis during acute and chronic intestinal inflammation is the intestinal myofibroblast. COX-2 expression has also been documented in these cells in colonic neoplasms. Thus an understanding of the regulation of COX-2 expression in human intestinal myofibroblasts is important. As an initial step toward this goal we have characterized IL-1alpha signaling pathways that induce COX-2 expression in cultured human intestinal myofibroblasts. IL-1 treatment resulted in a dramatic transcriptional induction of COX-2 gene expression. Activation of nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated protein kinase (ERK), p38, and protein kinase C (PKC) signaling pathways was each necessary for optimal COX-2 induction. In contrast to what occurs in other cell types, including other myofibroblasts such as renal mesangial cells, PKC inhibition did not prevent IL-1-induced NF-kappaB or mitogen activated protein kinase/ stress-activated protein kinase activation, suggesting a novel role for PKC isoforms during this process. The stimulatory effects of PKC, NF-kappaB, ERK-1/2, and presumably c-Jun NH(2)-terminal kinase activation were exerted at the transcriptional level, whereas p38 activation resulted in increased stability of the COX-2 message. We conclude that, in intestinal myofibroblasts, IL-1-mediated induction of COX-2 expression is a complex process that requires input from multiple signaling pathways. Each parallel pathway acts in relative autonomy, the sum of their actions culminating in a dramatic increase in COX-2 transcription and message stability.
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PMID:Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction. 1188 Feb 71

Lung injury induced by acute endotoxemia is associated with increased generation of inflammatory mediators such as nitric oxide and eicosanoids, which have been implicated in the pathophysiological process. Although production of these mediators by alveolar macrophages (AM) has been characterized, the response of type II cells is unknown and was assessed in the present studies. Acute endotoxemia caused a rapid (within 1 h) and prolonged (up to 48 h) induction of nitric oxide synthase-2 (NOS-2) in type II cells but a delayed response in AM (12-24 h). In both cell types, this was associated with increased nitric oxide production. Although type II cells, and to a lesser extent AM, constitutively expressed cyclooxygenase-2, acute endotoxemia did not alter this activity. Endotoxin administration had no effect on mitogen-activated protein kinase or protein kinase B-alpha (PKB-alpha) expression. However, increases in phosphoinositide 3-kinase and phospho-PKB-alpha were observed in type II cells. The finding that this was delayed for 12-24 h suggests that these proteins do not play a significant role in the regulation of NOS-2 in this model. After endotoxin administration to rats, a rapid (within 1-2 h) activation of nuclear factor-kappaB was observed. This response was transient in type II cells but was sustained in AM. Interferon regulatory factor-1 (IRF-1) was also activated rapidly in type II cells. In contrast, IRF-1 activation was delayed in AM. These data demonstrate that type II cells, like AM, are highly responsive during acute endotoxemia and may contribute to pulmonary inflammation.
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PMID:Activation of type II alveolar epithelial cells during acute endotoxemia. 1188 Mar 15

Endotoxin tolerance was initially described when it was observed that animals survived a lethal dose of bacterial endotoxin if they had been previously treated with a sublethal injection. In animal models, two phases of endotoxin tolerance are described, an early phase associated with altered cellular activation and a late phase associated with the development of specific antibodies against the polysaccharide side chain of Gram-negative organisms. Recently, there has been a tremendous resurgence of interest in the mechanisms responsible for altered responsiveness to bacterial endotoxin. Host immune cells, particularly macrophages and monocytes, that are exposed to endotoxin for 3 to 24 hrs are rendered "tolerant" and manifest a profoundly altered response when rechallenged with bacterial endotoxin or lipopolysaccharide. The "lipopolysaccharide-tolerant" phenotype is characterized by inhibition of lipopolysaccharide-stimulated tumor necrosis factor production, altered interleukin-1 and interleukin-6 release, enhanced cyclooxygenase-2 activation, inhibition of mitogen-activated protein kinase activation, and impaired nuclear factor-kappaB translocation. Human monocytes and macrophages can be induced to become tolerant, and there is increasing evidence that monocytic cells from patients with systemic inflammatory response syndrome and sepsis have many characteristics of endotoxin tolerance.
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PMID:Endotoxin tolerance: A review. 1189 6

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