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

Asthma is characterized by an irreversible subepithelial fibrosis with the appearance of myofibroblasts, which can be now considered important early participants in inflammatory responses as well as potential targets for anti-inflammatory drugs. In this study, we show that fluticasone propionate (FP), a powerful inhaled corticosteroid (ICS), displays novel anti-inflammatory effects on human lung fibroblasts during their myofibroblastic differentiation. Indeed, FP inhibits in lung myofibroblasts, at a very early stage of differentiation, the activation of Janus kinase/STAT pathways induced by IL-13 (tyrosine kinase 2, STAT1, STAT3, STAT6, mitogen-activated protein kinase). Contrarily, in mildly or fully differentiated myofibroblastic cultures, FP still displays a potential anti-inflammatory activity even if it only inhibits tyrosine kinase 2 phosphorylation. Moreover, FP inhibits constitutive and TGF-beta-induced expression of alpha-smooth muscle actin, the main marker of myofibroblastic differentiation, both in very early and in mild differentiated myofibroblasts. Finally, FP displays an additional powerful anti-inflammatory effect, decreasing nuclear translocation of NF-kappaB independent of the degree of myofibroblastic differentiation. These data 1) suggest that myofibroblasts are priority targets for ICS, which is able to revert them to a normal phenotype even if they appear to be already engaged in their differentiation, and 2) may help to explain why asthma is improved by an early ICS treatment, whereas advanced asthma is more resistant to these drugs.
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PMID:Novel anti-inflammatory effects of the inhaled corticosteroid fluticasone propionate during lung myofibroblastic differentiation. 1167 49

Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell-surface molecules. Blockade of RAGE has been reported to considerably improve liver function and accelerate regeneration after hepatectomy. The aim of this study was to investigate the cell type-specific expression of RAGE, and to examine whether transdifferentiation of hepatic stellate cells (HSC) into myofibroblasts (MFB) is associated with changes in RAGE expression. Northern blot analysis revealed that RAGE mRNA was exclusively expressed by HSC isolated from rat liver, while no transcripts were seen in hepatocytes, Kupffer cells, or sinusoidal endothelial cells. Expression of RAGE mRNA was up-regulated during transdifferentiation of HSC into MFB. Concomitantly, expression of RAGE protein was increased as confirmed by Western blotting and immunohistochemistry. As assessed by radioactive labeling, transforming growth factor beta(1) (TGF-beta(1)) induced a time-dependent 2- to 15-fold increase in the de novo synthesis of RAGE protein, which was completely abolished using PD098059, a specific inhibitor of the mitogen-activated protein kinase (MAPK) kinase. As shown by double-immunofluorescence staining, RAGE colocalized with alpha-smooth muscle actin, and immunoelectron microscopy demonstrated the most prominent labeling for RAGE at filopodial membranes of MFB. In conclusion, this study demonstrates that expression of RAGE is restricted to rat HSC, and that expression is up-regulated during activation of HSC and transition to MFB. The preferential immunogold labeling of RAGE to focal membrane areas of filopodia of MFB is suggestive of a role of RAGE in the spreading and migration of activated HSC/MFB, major players in liver fibrogenesis.
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PMID:Up-regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to myofibroblasts. 1167 65

Intestinal mucosal immunity is modulated by cytokine release from intestinal cells, but little is known about the relation between nutrient absorption and cytokine release. In this study, we examined how exposure to fatty acids affects the production of growth-regulated oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) and interleukin (IL)-6 in rat intestinal epithelial cells (IEC). The long-chain fatty acids, oleic, linoleic and arachidonic acids, and the middle-chain fatty acid octanoic acid were administered to subconfluent cultures of IEC-6 cells alone, or in combination with IL-1beta and transforming growth factor (TGF)-beta. The GRO/CINC-1 and IL-6 concentrations in culture media were determined by sandwich enzyme immunoassay. In epithelial cells, GRO/CINC-1 and IL-6 mRNA expression were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and mitogen-activated protein kinase (MAPK) activities determined by immunoblotting. Administration of long-chain fatty acids significantly increased the GRO/CINC-1 and IL-6 secretion into culture media, and this secretion was markedly increased (P < 0.05) in the presence of IL-1beta or TGF-beta. Octanoic acid had no effect on GRO/CINC-1 or IL-6 production. Furthermore, treatment with long-chain fatty acids significantly enhanced the GRO/CINC-1 and IL-6 expression that was induced by IL-1beta or TGF-beta. MAPK activity was significantly enhanced by treatment with long-chain fatty acids. Inhibitors of phospholipase C, protein kinase C or MAPK significantly reduced the fatty acid-induced increase in GRO/CINC-1 secretion, whereas a calcium/calmodulin inhibitor did not attenuate the secretion. These results suggest that long-chain fatty acids enhance cytokine release under conditions of inflammatory stimulation in the intestinal mucosa.
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PMID:Fatty acids enhance GRO/CINC-1 and interleukin-6 production in rat intestinal epithelial cells. 1169 23

Transforming growth factor (TGF)-beta is a natural and potent growth inhibitor of a variety of cell types, including epithelial, endothelial, and hematopoietic cells. The ability of TGF-beta to potently inhibit the growth of many solid tumors of epithelial origin, including breast and colon carcinomas, is of particular interest. However, many solid tumor cells become refractory to the growth inhibitory effects of TGF-beta due to defects in TGF-beta signaling pathways. In addition, TGF-beta may stimulate the invasiveness of tumor cells via the paracrine effects of TGF-beta. Accordingly, in order to develop more effective anticancer therapeutics, it is necessary to determine the TGF-beta signal transduction pathways underlying the growth inhibitory effects and other cellular effects of TGF-beta in normal epithelial cells. Thus far, two primary signaling cascades downstream of the TGF-beta receptors have been elucidated, the Sma and mothers against decapentaplegic homologues and the Ras/mitogen-activated protein kinase pathways. The major objective of this review is to summarize TGF-beta signaling in epithelial cells, focusing on recent advances involving the Sma and mothers against decapentaplegic homologues and Ras/mitogen-activated protein kinase pathways. This review is particularly timely in that it provides a comprehensive summary of both signal transduction mechanisms and the cell cycle effects of TGF-beta.
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PMID:Transforming growth factor-beta signal transduction in epithelial cells. 1170 92

Apoptosis contributes to myocardial cell death during ischemia and reperfusion, especially during reperfusion. Growth factor "survival" signaling attenuates apoptosis. We therefore examined the effects of transforming growth factor-beta1 (TGF-beta1) on reperfusion injury and assessed the role of p42/p44 MAPK signaling in TGF-beta1-induced protection. Rat ventricular myocytes were subjected to hypoxia and reoxygenation. TGF-beta1 (0.2 ng/ml) was applied to cells during reoxygenation and the extent of apoptosis was determined by TUNEL and annexin V binding assays. Further studies were conducted in intact rat hearts subjected to regional ischemia and reperfusion. TGF-beta1 (0.2 ng/ml) was perfused during early reperfusion. In cells, incubation with TGF-beta1 (0.2 ng/ml) during reoxygenation attenuated the extent of cell membrane damage (trypan blue uptake) and also reduced the numbers of TUNEL-and annexin V-positive cells. Reduction of apoptosis was abrogated by PD98059 (5 microM), an inhibitor of p42/p44 MAPK activation. TGF-beta1 activated p42/p44 MAPK transiently in normoxic myocytes. When intact hearts received TGF-beta1 (0.2 ng/ml) during early reperfusion, infarct size was reduced from 39.4 +/- 3.1% to 17.3 +/- 3.1% (p < 0.01). This protective action of TGF-beta1 was abrogated by PD98059. These studies are the first to show that TGF-beta attenuates cardiac myocyte apoptosis during early reperfusion and limits infarct size through p42/p44 MAPK activation.
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PMID:Cardioprotective effects of transforming growth factor-beta1 during early reoxygenation or reperfusion are mediated by p42/p44 MAPK. 1170 97

Smad7 transcription is known to be regulated by TGF-beta to form a negative-feedback loop of TGF-beta-mediated biological responses. In this study, we sought to determine whether other signaling cascades, especially mitogen-activated protein (MAP) kinases, might be involved in the transcriptional regulation of Smad7. Hyperosmolarity (500 mOsm/kg H(2)O) or anisomycin (10 microg/ml) potentiated TGF-beta-induced increases of Smad7 mRNA abundance in normal rat kidney fibroblasts. SB203580 (10 microM) treatment had no effect on basal and TGF-beta-induced Smad7 mRNA abundance, and the overexpression of kinase-negative ATF2 had no effect on Smad7 promoter activity. On the other hand, overexpression of dominant-negative JNK and dominant-negative c-Jun significantly attenuated the TGF-beta-induced increases of Smad7 mRNA abundance and promoter activity, respectively. Mutations of the AP-1 element near the Smad-binding element in the rat Smad7 promoter also completely abolished TGF-beta-induced Smad7 promoter activity. These results suggested that the JNK cascade, not p38 kinase, cooperated with the Smad signaling to induce Smad7 transcription through the AP-1 element. Serum treatment (10%) attenuated the TGF-beta-induced Smad7 mRNA increase, and PD98059 (30 microM) treatment increased the basal and TGF-beta-induced Smad7 promoter activity. Gel shift analysis revealed that serum treatment decreased the amount of nuclear Smad complex that PD98059 treatment was shown to restore. These results indicated that ERK activation negatively regulated Smad7 transcription possibly by inhibiting translocation of Smad complex to nuclei. In conclusion, JNK cascade and ERK cascade are important positive and negative regulators of Smad7 transcription, respectively.
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PMID:Involvement of MAP kinase cascades in Smad7 transcriptional regulation. 1171 83

Diabetic nephropathy seems to occur as a result of an interaction of metabolic and haemodynamic factors. Glucose dependent pathways are activated within the diabetic kidney. These include increased oxidative stress, renal polyol formation and accumulation of advanced glycated end-products. Haemodynamic factors are also implicated in the pathogenesis of diabetic nephropathy and include increased systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin system and endothelin. These haemodynamic pathways, independently and with metabolic pathways, activate intracellular second messengers such as protein kinase C and MAP kinase, nuclear transcription factors such as NF-kappaB and various growth factors such as the prosclerotic cytokine, TGF-beta and the angiogenic, permeability enhancing growth factor, VEGF. These pathways ultimately lead to increased renal albumin permeability and extracellular matrix accumulation which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. Therapeutic strategies involved in the management and prevention of diabetic nephropathy include currently available treatments such as intensified glycaemic control and antihypertensive agents, particularly those which interrupt the renin-angiotensin system. More novel strategies to influence vasoactive hormone action or to inhibit various metabolic pathways such as inhibitors of advanced glycation, specific protein kinase C isoforms and aldose reductase are at present under experimental and clinical investigation. It is predicted that multiple therapies will be required to reduce the progression of diabetic nephropathy.
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PMID:Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. 1171 27

Smad proteins activated by TGF-beta form complexes with Smad4. Upon activation, these complexes translocate to the nucleus of the cell, where they induce transcription of genes related to inhibition of cell growth, cell differentiation and apoptosis. We investigated the role of Smads in the TGF-beta-mediated signal-transduction cascade in 4 human cervical cancer cell lines: HeLa, Caski, HT-3 and SiHa. Based on our results, SiHa cells show low mRNA expression of mutated Smad4 (Gly(230)Ala, Ala(488)Val) and of Smads 2, 3, 5 and 6. SiHa cells were likewise defective in TGF-beta signaling, as evidenced by a lack of significant growth inhibition following TGF-beta treatment. In addition, TGF-beta did not induce transcription of the PAI-1 gene or change Smad protein levels. Introduction of Smad3 and/or Smad4 into SiHa cells restored TGF-beta signaling, as determined by activation of the 3TP-lux reporter gene and by prominent apoptotic cell death with PAI-1 induction. Analysis of the downstream targets activated by TGF-beta yielded rapid activation of p38 with subsequent phosphorylation of the transcription factor ATF-2 but unchanged SAPK/JNK activation in the 4 cervical cancer cell lines. Our findings demonstrate that (i) decrease of Smad4 mRNA expression is closely associated with defective TGF-beta response and lack of growth inhibition, (ii) activation of PAI-1 by TGF-beta may be Smad4-dependent and (iii) the Smad and the p38 cascades are triggered by TGF-beta independently of each other in human cervical cancer.
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PMID:Aberrant expression of Smad4 results in resistance against the growth-inhibitory effect of transforming growth factor-beta in the SiHa human cervical carcinoma cell line. 1174 35

In our previous study, we demonstrated that porcine enamel matrix derivative (EMD) induces p21WAF1/cip1 within 8 hours and subsequently arrests the cell cycle of human oral epithelial cells in G1 phase. In contrast, EMD markedly stimulates the proliferation of gingival fibroblasts without inducing p21WAF1/cip1. To investigate the mechanism of how EMD produces these differential effects, we have focused on the initial response of these two cell types to EMD. In epithelial cell cultures, EMD stimulated cytoskeletal actin polymerization within 30 min and promoted cell adhesion in our experimental system. EMD failed to stimulate either intracellular Ca2+ mobilization or cAMP production in either cell type. In both epithelial and fibroblastic cells, EMD (25-100 microgram/ml) rapidly produced dose-dependent phosphorylation of the mitogen-activated protein kinase (MAPK) family: extracellular signal response kinase (ERK), p38-MAPK (p38-K), and c-Jun-terminal kinase/stress-activated protein kinase (JNK). However, neither inhibitors of MEK (ERK kinase) nor p38-K could block EMD's anti-proliferative action on epithelial cells. On the other hand, EMD rapidly stimulated translocation of smad2 into the nucleus in both cell types. Spurred by this finding, we assayed for TGF-beta1, a ligand for one receptor associated with smad2 activation, and detected significant levels in EMD preparations. The sum of these pharmacological findings indicates that EMD contains at least one bioactive factor, which is most probably TGF-beta1 (or TGF-beta-like substances). In conjunction with the similarities in the differential growth-modulating actions between EMD and what is known for TGF-beta, we suggest that TGF-beta might act as the principal growth regulating agent of oral fibroblastic and epithelial cell types in EMD despite being present in only low levels.
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PMID:Enamel matrix derivative (EMDOGAIN) rapidly stimulates phosphorylation of the MAP kinase family and nuclear accumulation of smad2 in both oral epithelial and fibroblastic human cells. 1176 72

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is a potent inhibitor of activated matrix metalloproteinases such as gelatinase and collagenase, and thus helps to control extracellular matrix metabolism and deposition by connective tissue cells. We examined the responsiveness of the expression of TIMP-2 to various cytokines in dermal fibroblasts and studied the regulatory and signaling mechanisms of the response. TIMP-2 protein and mRNA expression was induced by IL-4 in a dose- and time-dependent manner, but not by TGF-beta, oncostatin M, or IL-6. IL-4 induction of TIMP-2 expression was dependent upon transcription. The p38 mitogen-activated protein kinase (MAPK) inhibitors SB202190 and SB203580 suppressed IL-4-induced TIMP-2 expression, suggesting the involvement of p38 MAP kinase in the signaling of IL-4 leading to TIMP-2 expression. Immunoblotting analysis using a specific Ab against phosphorylated p38 MAP kinase (Thr(180)/Tyr(182)) showed that IL-4 induced phosphorylation of p38 MAP kinase in human dermal fibroblasts. Furthermore, the p38 MAP kinase assay showed that IL-4 induces p38 MAPK activation in human dermal fibroblasts. The expression of the dominant-negative mutant p38 MAPK represses the IL-4-induced TIMP-2 expression in human dermal fibroblasts. Thus, IL-4 can potentially alter the dermal matrix metabolism by regulating TIMP-2.
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PMID:IL-4 up-regulates the expression of tissue inhibitor of metalloproteinase-2 in dermal fibroblasts via the p38 mitogen-activated protein kinase dependent pathway. 1182 24


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