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)

Hypoxia causes several renal tubular dysfunctions, including abnormal handling of potassium and sodium and increased blood pressure. Therefore, we investigated the impact of hypoxia on 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) enzyme, a crucial prereceptor gatekeeper for renal glucocorticosteroid-mediated mineralocorticoid action. The effect of hypoxia was assessed in vitro by incubating LLC-PK1 cells with antimycin A, an inhibitor of mitochondrial oxidative phosphorylation. Antimycin A induced a dose- and time-dependent reduction of 11beta-HSD2 activity. The early growth response gene, Egr-1, a gene known to be stimulated by hypoxia was investigated because of a potential Egr-1 binding site in the promoter region of 11beta-HSD2. Antimycin A induced Egr-1 protein and Egr-1-regulated luciferase gene expression. This induction was prevented with the MAPKK inhibitor PD 98059. Overexpression of Egr-1 reduced endogenous 11beta-HSD2 activity in LLC-PK1 cells, indicating that MAPK ERK is involved in the regulation of 11beta-HSD2 in vitro. In vivo experiments in rats revealed that Egr-1 protein increases, whereas 11beta-HSD2 mRNA decreases, in kidney tissue after unilateral renal ischemia and in humans the renal activity of 11beta-HSD2 as assessed by the urinary ratio of (tetrahydrocortisol+5alpha-tetrahydrocortisol)/tetrahydrocortisone declined when volunteers were exposed to hypoxemia at high altitude up to 7000 m. Thus, hypoxia decreases 11beta-HSD2 transcription and activity by inducing Egr-1 in vivo and in vitro. This mechanism might account for enhanced renal sodium retention and hypertension associated with hypoxic conditions.
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PMID:Hypoxia causes down-regulation of 11 beta-hydroxysteroid dehydrogenase type 2 by induction of Egr-1. 1262 38

The adipocyte enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) amplifies local glucocorticoid action by generating active glucocorticoids from inactive metabolites and has emerged as a key player in the pathogenesis of central obesity and metabolic syndrome. However, the regulation of adipocyte 11beta-HSD1 is incompletely understood. Therefore, the present study was designed to investigate the effects of insulin and glucocorticoid as well as their underlying molecular mechanisms on 11beta-HSD1 activity and expression in 3T3-L1 adipocytes and determine whether the in vitro findings could be confirmed in vivo. Our main in vitro findings are 1) insulin stimulated whereas dexamethasone inhibited 11beta-HSD1 activity and expression in a time- and concentration-dependent manner; 2) the effect of dexamethasone was mimicked by both cortisol and corticosterone but blocked by the glucocorticoid receptor antagonist RU486; 3) the p38 MAPK inhibitor SB220025, but not the ERK inhibitor U0126 or the phosphatidylinositol 3-kinase inhibitor LY294002, prevented insulin stimulation of 11beta-HSD1 activity; and 4) although dexamethasone did not alter the half-life of 11beta-HSD1 mRNA, insulin doubled it. Taken together, these in vitro results demonstrate that insulin stimulates adipocyte 11beta-HSD1 through a posttranscriptional mechanism that involves activation of the p38 MAPK signaling pathway, whereas dexamethasone exerts an opposite effect by a glucocorticoid receptor-mediated transcriptional mechanism. In contrast, both insulin and dexamethasone augmented 11beta-HSD1 activity and expression in rat white adipose tissue in vivo, thus confirming the role of insulin but revealing a fundamental difference regarding the role of dexamethasone in regulating adipocyte 11beta-HSD1 between the two model systems.
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PMID:Insulin and dexamethasone dynamically regulate adipocyte 11beta-hydroxysteroid dehydrogenase type 1. 1846 33

The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of inactive to active glucocorticoids. 11beta-HSD1 plays a crucial role in the pathogenesis of obesity and controls glucocorticoid actions in inflammation. Several studies have demonstrated that TNF-alpha increases 11beta-HSD1 mRNA and activity in various cell models. Here, we demonstrate that mRNA and activity of 11beta-HSD1 is increased in liver tissue from transgenic mice overexpressing TNF-alpha, indicating that this effect also occurs in vivo. To dissect the molecular mechanism of this increase, we investigated basal and TNF-alpha-induced transcription of the 11beta-HSD1 gene (HSD11B1) in HepG2 cells. We found that TNF-alpha acts via p38 MAPK pathway. Transient transfections with variable lengths of human HSD11B1 promoter revealed highest activity with or without TNF-alpha in the proximal promoter region (-180 to +74). Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region. Gel shift and RNA interference assays revealed the involvement of mainly C/EBPalpha, but also C/EBPbeta, in basal and only of C/EBPbeta in the TNF-alpha-induced HSD11B1 expression. Chromatin immunoprecipitation assay confirmed in vivo the increased abundance of C/EBPbeta on the proximal HSD11B1 promoter upon TNF-alpha treatment. In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter. To our knowledge, this is the first study showing involvement of p38 MAPK in the TNF-alpha-mediated 11beta-HSD1 regulation, and that TNF-alpha stimulates enzyme activity in vivo.
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PMID:Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells. 1908 56

The anti-inflammatory actions of endogenous glucocorticoids (GCs) are regulated by the activities of the GC-activating and -inactivating enzymes, 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-1 and 11beta-HSD2, respectively, that catalyze the interconversion of the inert GC, cortisone, and its bioactive derivative, cortisol. Proinflammatory cytokines regulate 11beta-HSD1 expression in various cell types and thereby modulate the bioavailability of cortisol to the glucocorticoid receptor (GR). Since endogenous GCs reportedly attenuate the airway asthmatic response to allergen exposure, we investigated whether airway smooth muscle (ASM) exhibits cytokine-induced changes in 11beta-HSD1 expression that enable the ASM to regulate its own bioavailability of GC and, accordingly, the protective effect of GR signaling on airway function under proasthmatic conditions. Human ASM cells exposed to the primary proasthmatic T helper type 2 (Th2) cytokine, IL-13, exhibited upregulated expression of 11beta-HSD1, an effect that was attributed to activation of the transcription factor, AP-1, coupled to MAPK signaling via the ERK1/2 and JNK pathways. The induction of 11beta-HSD1 expression and its oxoreductase activity by IL-13 (also IL-4) served to amplify the conversion of cortisone to cortisol by the cytokine-exposed ASM and, hence, heighten GR-mediated transcriptional activation. Extended studies demonstrated that this amplified 11beta-HSD1-dependent GC activation enabled physiologically relevant concentrations of cortisone to exert enhanced protection of ASM tissues from the proasthmatic effects of IL-13 on ASM constrictor and relaxation responsiveness. Collectively, these novel findings identify a Th2 cytokine-driven homeostatic feedback mechanism in ASM that enhances its responsiveness to endogenous GCs by upregulating 11beta-HSD1 activity, thereby curtailing the adverse effects of the proasthmatic cytokine on airway function.
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PMID:Th2 cytokine-induced upregulation of 11beta-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function. 1925 40

Increasing evidence suggests that aldosterone is implicated in the pathogenesis of cardiovascular diseases. We examined whether aldosterone contributes to the cyclic stretch (CS)-induced reactive oxygen species (ROS) generation in rat aortic smooth muscle cells (RASMCs). RASMCs were exposed to uniaxial CS and thereafter collected to evaluate the expressions of mRNA or protein relating aldosterone synthesis and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. CS strength-dependently enhanced NADPH oxidase activity. CS induced cytochrome P450 aldosterone synthase (CYP11B2) and increased aldosterone synthesis but did not influence the levels of 11beta-hydroxysteroid dehydrogenase 2 and mineralocorticoid receptor (MR). This CYP11B2 induction was almost completely suppressed by treatment with an extracellular signal-regulated kinase (ERK) inhibitor, U0126, whereas olmesartan, an angiotensin II (Ang II) receptor blocker (ARB), only partially suppressed CS-induced CYP11B2 expression and ERK phosphorylation. A selective MR antagonist, eplerenone (10 micromol l(-1)), significantly attenuated the CS-induced NADPH oxidase activation even in the presence of ARBs. In conclusion, aldosterone synthesis, which is partially independent of Ang II, may have an important role in CS-stimulated ROS generation in cultured RASMCs. We also suggest the potential benefit of eplerenone in the treatment of cardiovascular diseases.
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PMID:The involvement of aldosterone in cyclic stretch-mediated activation of NADPH oxidase in vascular smooth muscle cells. 1947 13

Increased expression and activity of the intracellular glucocorticoid-reactivating enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) contribute to dysfunction of adipose tissue. Although the pathophysiological role of 11 beta-HSD1 in mature adipocytes has long been investigated, its potential role in preadipocytes still remains obscure. The present study demonstrates that the expression of 11 beta-HSD1 in preadipocyte-rich stromal vascular fraction (SVF) cells in fat depots from ob/ob and diet-induced obese mice was markedly elevated compared with lean control. In 3T3-L1 preadipocytes, the level of mRNA and reductase activity of 11 beta-HSD1 was augmented by TNF-alpha, IL-1 beta, and LPS, with a concomitant increase in inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein-1 (MCP-1), or IL-6 secretion. Pharmacological inhibition of 11 beta-HSD1 and RNA interference against 11 beta-HSD1 reduced the mRNA and protein levels of iNOS, MCP-1, and IL-6. In contrast, overexpression of 11 beta-HSD1 further augmented TNF-alpha-induced iNOS, IL-6, and MCP-1 expression. Moreover, 11 beta-HSD1 inhibitors attenuated TNF-alpha-induced phosphorylation of NF-kappaB p65 and p38-, JNK-, and ERK1/2-MAPK. Collectively, the present study provides novel evidence that inflammatory stimuli-induced 11 beta-HSD1 in activated preadipocytes intensifies NF-kappaB and MAPK signaling pathways and results in further induction of proinflammatory molecules. Not limited to 3T3-L1 preadipocytes, we also demonstrated that the notion was reproducible in the primary SVF cells from obese mice. These findings highlight an unexpected, proinflammatory role of reamplified glucocorticoids within preadipocytes in obese adipose tissue.
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PMID:Glucocorticoid reamplification within cells intensifies NF-kappaB and MAPK signaling and reinforces inflammation in activated preadipocytes. 1977 25

Mineralocorticoid receptor (MR) activation by aldosterone controls salt homeostasis and inflammation in several tissues and cell types. Whether or not a functional MR exists in polymorphonuclear neutrophils is unknown. We investigated the hypothesis that aldosterone modulates inflammatory neutrophil responses via the MR. By flow cytometry, Western blot analysis, and microscopy, we found that neutrophils possess MR. Preincubation with aldosterone (10(-11) to 10(-6) M) dose-dependently inhibited nuclear factor kappaB activation in interleukin (IL)-8- and granulocyte/macrophage colony-stimulating factor-treated neutrophils on fibronectin by IkappaBalpha Western blotting, electrophoretic mobility shift assay, and RT-PCR for IkappaBalpha mRNA. Aldosterone had no effect on tumor necrosis factor alpha- and lipopolysaccharide-mediated nuclear factor kappaB activation or on IL-8- and granulocyte/macrophage colony-stimulating factor-induced extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, or phosphatidylinositol 3-kinase/Akt activation. Spironolactone prevented nuclear factor kappaB inhibition, indicating an MR-specific aldosterone effect. By RT-PCR, we found that neutrophils have 11beta-hydroxysteroid dehydrogenase. Tumor necrosis factor alpha, which is controlled by nuclear factor kappaB, increased in the cell supernatant with IL-8 treatment. Aldosterone completely prevented this effect. RT-PCR showed a strong tumor necrosis factor alpha mRNA increase with IL-8 that was blocked by aldosterone, excluding the possibility that the tumor necrosis factor alpha increase was merely a consequence of secretion. Finally, conditioned medium from IL-8-treated neutrophils increased intercellular adhesion molecule-1 expression on endothelial cells and subsequently the adhesion of IL-8-treated neutrophils to endothelial cells. These effects were reduced when conditioned medium from aldosterone-pretreated neutrophils was used, and spironolactone blocked the aldosterone effect. Our data indicate that a functional MR exists in neutrophils mediating antiinflammatory effects that are at work when neutrophils interact with endothelial cells. These data could be relevant to MR-blockade treatment protocols.
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PMID:Aldosterone abrogates nuclear factor kappaB-mediated tumor necrosis factor alpha production in human neutrophils via the mineralocorticoid receptor. 2006 53