Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The innate immune system plays a crucial role in protecting the host against infectious microorganisms. An inappropriate control of this system may have profound consequences, because of the maintained production of specific proinflammatory molecules. Glucocorticoids are the most efficient endogenous molecules that provide negative feedback on proinflammatory signaling and gene expression. Here we show that activation of this system is not detrimental for the brain but a profound neurodegeneration takes place in animals treated with the glucocorticoid receptor inhibitor Mifepristone (RU486). This drug increased the inflammatory reaction induced by a single intracerebral bolus of lipopolysaccharide (LPS). Inhibition of tumor necrosis factor alpha (TNF-alpha) totally abolished the neurotoxic effect of the endotoxin, and chronic infusion of the cytokine mimicked the treatment combining RU486 and LPS. The neuronal damage caused by TNF-alpha is dependent on both nitric oxide and caspase pathways. In controlling the cerebral innate immunity and microglial TNF-alpha production, glucocorticoids play a major role in protecting the brain against bacterial cell wall components.
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PMID:Glucocorticoids play a fundamental role in protecting the brain during innate immune response. 1284 54

(1) Septic shock represents an important risk factor for patients critically ill. This pathology has been largely demonstrated to be a result of a myriad of events. Glucocorticoids represent the main pharmacological therapy used in this pathology. (2) Previously we showed that ATP-sensitive potassium (KATP) channels are involved in delayed vascular hyporeactivity in rats (24 h after Escherichia coli lipopolysaccharide (LPS) injection). In LPS-treated rats, we observed a significant hyporeactivity to phenylephrine (PE) that was reverted by glybenclamide (GLB), and a significant increase in cromakalim (CRK)-induced hypotension. (3) We evaluated the effect of dexamethasone (DEX 8 mg kg-1 i.p.) whether on hyporeactivity to PE or on hyperreactivity to CRK administration, in vivo, in a model of LPS (8 x 106 U kg-1 i.p.)-induced endotoxemia in urethane-anaesthetised rats. (4) DEX treatment significantly reduced, in a time-dependent manner, the increased hypotensive effect induced by CRK in LPS-treated rats. This effect was significantly (P<0.05) reverted by the glucocorticoid receptor antagonist RU38486 (6.6 mg kg-1 i.p.). (5) GLB-induced hypertension (40 mg kg-1 i.p.), in LPS-treated rats, was significantly inhibited by DEX if administered at the same time of LPS. (6) Simultaneous administration of DEX and LPS to rats completely abolished the hyporeactivity to PE observed after 24 h from LPS injection. (7) In conclusion, our results suggest that the beneficial effect of DEX in endotoxemia could be ascribed, at least in part, to its ability to interfere with KATP channel activation induced by LPS. This interaction may explain the improvement of vascular reactivity to PE, mediated by DEX, in LPS-treated rats, highlighting a new pharmacological activity to the well-known anti-inflammatory properties of glucocorticoids.
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PMID:Dexamethasone improves vascular hyporeactivity induced by LPS in vivo by modulating ATP-sensitive potassium channels activity. 1296 38

Stress is a potential factor causing increased susceptibility of fish to pathogens. In this study, stress-induced immunological changes that may contribute to a decreased immune status were investigated. A 3 h drop in ambient water temperature of 9 degrees C was used as a relative mild and acute stress model for carp. Effects of this stressor on the dynamics of leucocyte populations were determined with specific monoclonal antibodies. The relative number of circulating B-lymphocytes in the total leucocyte population decreased significantly within 4 h after the onset of single or multiple cold shocks. This decrease was reversible, as B-lymphocyte numbers were restored within 24 h. Most probably, a redistribution of B-lymphocytes contributed to this phenomenon. In head kidney, an increase was measured in the relative number of B-lymphocytes. Granulocyte numbers showed opposite reactions: the percentage of granulocytes in the total leucocyte population nearly doubled in circulation and decreased significantly in the head kidney. This demonstrates that in vivo, a mild stressor differentially alters the distribution of leucocytes. In stressed carp, the percentage of apoptotic lymphocytes in blood is significantly higher compared with the unstressed animals. B-lymphocytes as well as Ig- lymphoid cells contributed to this increased apoptosis. Labelling of blood lymphocytes with a polyclonal antiserum against the glucocorticoid receptor also showed, besides B-lymphocytes, part of the Ig- lymphoid cell population to be glucocorticoid receptor positive. As the distribution of B-lymphocytes was substantially affected, the effect of temperature stress on T-lymphocyte-independent (trinitrophenyl-lipopolysaccharide) and T-lymphocyte-dependent (dinitrophenyl-keyhole limpet hemocyanin) humoral antibody responses was determined. Kinetics of the primary antibody response to the T-lymphocyte-independent antigen showed lower antibody titres in stressed carp during the onset of the immune response, implying a slower development of the antibody response against the T-lymphocyte-independent antigen.
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PMID:Multiple acute temperature stress affects leucocyte populations and antibody responses in common carp, Cyprinus carpio L. 1455 Jun 66

Brain inflammation is accompanied by transection of axons and death of neurons in the acute lesions of multiple sclerosis. We explored mechanisms of inflammatory damage to neurons in vitro using cocultures of rat embryonal cortical neurons with microglia activated by interferon-gamma (IFNgamma) and lipopolysaccharide (LPS). Previously, we have demonstrated that microglia are highly toxic to neurons and that nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) is necessary and sufficient to mediate this toxicity. Here, we show that addition of dexamethasone (1 micro M) to activated cocultures provides effective neuroprotection. We demonstrate that dexamethasone down-regulates NO production of primary microglia by approximately 50% and reduces steady-state iNOS protein and mRNA expression by approximately 70%. These changes were reversed by the glucocorticoid receptor blocker RU-486. Furthermore, we analysed the stability of iNOS protein and show that whilst inhibitors of the proteasome blocked iNOS degradation they did not reverse the dexamethasone effect. Our results indicate that the main mechanism of corticosteroid activity on iNOS is reduction in protein synthesis, not destabilization as previously suggested.
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PMID:Decreased iNOS synthesis mediates dexamethasone-induced protection of neurons from inflammatory injury in vitro. 1462 53

Previously, we have found that some antipsychotic drugs are able to inhibit glucocorticoid receptor (GR)-mediated gene transcription. Since these drugs are known not only to inhibit hypothalamic-pituitary-adrenal (HPA) axis activity, but also to modulate the immunological system, the aim of the present study was to compare the effect of sulpiride and clozapine on GR function under basal culture conditions and during activation by lipopolysaccharide (LPS). The effect of clozapine and sulpiride alone and with LPS, the immune system activator, on glucocorticoid-mediated gene transcription was investigated in fibroblast cells, stably transfected with a mouse mammary tumor virus--chloramphenicol acetyltransferase plasmid (LMCAT cells). Treatment of the cells with clozapine (3-10 microM) for 2 days significantly and in concentration-dependent manner decreased the chloramphenicol acetyltransferase (CAT) activity, while sulpiride (1, 3, 5 and 10 microM) was without any effect. LPS (1 microg/ml) given alone inhibited the corticosterone-induced gene transcription by ca. 35%. Clozapine (3, 5 and 10 microM) inhibited the effect of LPS (1 microM), while sulpiride, which alone had no effect on GR function, enhanced LPS (1 microM) action. The obtained results indicate that inhibition of GR-mediated gene transcription by LPS and clozapine can be a mechanism by which these compounds blocked some effects induced by glucocorticoids. Opposite effect of clozapine and sulpiride on LPS action may result from their distinct effect on activity of some kinases involved in regulation of GR transcriptional function and may determine their utility in the treatment of schizophrenia with or without immune system activation.
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PMID:Opposite effects of clozapine and sulpiride on the lipopolysaccharide-induced inhibition of the GR-mediated gene transcription in fibroblast cells. 1473 Jan 15

Heat shock protein 90 (Hsp90) regulates the functions of glucocorticoid receptor (GR). Hsp90 inhibitors geldanamycin (GA) and radicicol (Rad) have been studied as anti-inflammatory agents; however, their effects on glucocorticoid-mediated anti-inflammatory mechanism are not known. In the present study, we examined the effects of dexamethasone (Dex) and Hsp90 inhibitors, alone and in combination, on the activation of GR and proinflammatory transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). In cell-based reporter assay, Hsp90 inhibitors inhibited Dex-induced nuclear import and transcriptional activity of GR. Both tumor necrosis factor-alpha-activated NF-kappaB and phorbol ester-activated AP-1 were inhibited by Dex and Hsp90 inhibitors alone. When the cells were treated with a combination of these drugs, the inhibitory effect of Dex was significantly attenuated by Hsp90 inhibitors. We further examined the effects of Dex and Rad on lipopolysaccharide-induced gene expressions of the proinflammatory cytokine interleukin (IL)-1beta in macrophages. Dex, but not Rad, inhibited IL-1beta expression. Rad concentration-dependently attenuated the inhibitory effect of Dex. These results suggest that Hsp90 inhibitor itself inhibits the activation of NF-kappaB and AP-1, however, impedes Dex-induced inhibition of IL-1beta induction by attenuating Dex-mediated activation of GR and inhibition of the proinflammatory transcription factors.
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PMID:Hsp90 inhibitors attenuate effect of dexamethasone on activated NF-kappaB and AP-1. 1496 93

Functional roles of the 3'-untranslated region (3'-UTR) of the human Cyclooxygenase-2 (COX-2) gene were evaluated by transient transfection using luciferase (Luc) reporter vectors into bovine arterial endothelial cells (BAEC). Insertion of the 3'-UTR into the downstream of a Luc coding region resulted in decreased reporter activity (23%), although insertion into the upstream was no effect. The reporter activity of the downstream insertion but not the upstream insertion was induced by bacterial lipopolysaccharide (LPS). Moreover, LPS selectively stabilized COX-2 mRNA. Next, to evaluate the role of the 3'-UTR together with glucocorticoid receptor (GR), a GR-expression vector was cotransfected with the reporter vector of the downstream insertion of the 3'-UTR. As a result, the LPS-induced reporter activity was suppressed by dexamethasone in a dose-dependent manner. These data suggest that the 3'-UTR of the COX-2 gene is involved in not only the induction by LPS but also the suppression by DEX of COX-2 expression at the post-transcriptional level.
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PMID:Involvement of the 3'-untranslated region of cyclooxygenase-2 gene in its post-transcriptional regulation through the glucocorticoid receptor. 1501 Feb 61

The use of chronic glucocorticoid (GC) therapy for the treatment of inflammatory diseases is limited by associated metabolic side effects, including muscle atrophy. Therefore, selective glucocorticoid receptor-(GR)-binding ligands that maintain anti-inflammatory activity and demonstrate diminished side-effect profiles would have great therapeutic utility. In this work, we use Taqman PCR and ELISA methods to show that GCs can inhibit basal, and lipopolysaccharide (LPS)-stimulated levels of cytokines IL-6 and TNFalpha, and also the chemokine MCP-1 in a non-inflammatory system such as primary human skeletal muscle cells. In the murine C2C12 skeletal muscle cell line we observe a similar effect of GCs on IL-6 and MCP-1; however, in contrast to previous reports, we observe a time-dependent repression of TNFalpha. Furthermore, in skeletal muscle cells, concomitant with cytokine repression, GCs transcriptionally induce glutamine synthetase (GS), a marker for muscle wasting, in an LPS independent manner. Similarly, administration of dexamethasone to mice, previously administered LPS, results in an increase in GS and an inhibition of TNFalpha and MCP-1 in skeletal muscle tissue. Thus, skeletal muscle cells and tissues present a novel system for the identification of selective GR-binding ligands, which simultaneously inhibit cytokine expression in the absence of GS induction.
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PMID:Skeletal muscle: a dual system to measure glucocorticoid-dependent transactivation and transrepression of gene regulation. 1508 51

Enhanced corticosterone release by female compared to male rats under basal and stress conditions is well documented. The demonstration that gonadectomy enhances stress-induced corticosterone secretion in male rats, but reduces such levels in female rats, suggests a causal association between gonadal steroids and corticosterone release. The present study examined the corticosterone profile of sham gonadectomized and gonadectomized female and male rats under basal and stress conditions. An automated sampling system collected blood from each freely moving, unanaesthetized rat every 10 min (i) over a 24-h period; (ii) following noise stress; and (iii) following an immune-mediated stress (lipopolysaccharide, LPS). Plasma was analysed for corticosterone content using radioimmunoassay. Castration resulted in a significant increase in basal corticosterone release compared to the sham-castrated male rats. Pulsar analysis revealed a significant two-fold increase in the number of corticosterone pulses over 24 h. Corticosterone increases in response to noise stress and to LPS injection were enhanced following castration. Conversely, ovariectomy resulted in a two-fold reduction in the number of corticosterone pulses as well as the stress response compared to sham-ovariectomized female rats. Arginine vasopressin (AVP), corticotrophin-releasing hormone (CRH) and glucocorticoid receptor mRNAs in the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary were analysed post-LPS administration by in situ hybridization. Significantly higher values were found for AVP, CRH and POMC mRNAs examined for sham females and castrated males compared to sham males and ovariectomized females. This study confirms previous reports concerning the influence of gonadal factors in regulating HPA axis activity and stress responsiveness. The present results extend these observations to the regulation of the dynamic pattern of corticosterone release under basal conditions and suggests that this alteration in pulsatility is important for the differences in stress responsiveness when comparing males and females.
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PMID:Gonadectomy reverses the sexually diergic patterns of circadian and stress-induced hypothalamic-pituitary-adrenal axis activity in male and female rats. 1518 26

Social stress during early postnatal life often results in long-term effects on neuroendocrine and immune adaptation mechanisms. Therefore, the aim of the present study was to determine the influence of a 2-h daily social isolation from Day 3 to Day 11 on the acute and long-term proinflammatory and neuroendocrine responses of piglets challenged with the bacterial endotoxin lipopolysaccharide (LPS; 100 microg/kg body weight). Peripheral LPS administration significantly increased plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), ACTH and cortisol in isolated and control pigs. However, the activity of the hypothalamic-pituitary-adrenal (HPA) axis after LPS stimulation was not significantly affected by isolation treatment, whereas the prior social isolation diminished the plasma TNF-alpha response to LPS 1 day as well as 45 days after the isolation period. The hippocampal TNF-alpha concentration in response to LPS was also reduced in priorly isolated pigs compared to control animals. Furthermore, the significant increase of TNF-alpha in the spleen caused by LPS was associated with a dramatic decrease in glucocorticoid receptor (GR) binding. The GR binding in hippocampus was increased in isolated pigs and was significantly decreased after LPS injection. In addition, the repeated isolation stressor was shown to increase hippocampal levels of interleukin-1beta (IL-1beta). The present results indicate that repeated social isolation of neonatal pigs may cause long-term effects on proinflammatory regulation at the periphery and in the brain following immune challenge with particular importance of TNF-alpha in mediating these interactions.
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PMID:Effects of postnatal social isolation on hormonal and immune responses of pigs to an acute endotoxin challenge. 1527 16


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