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

Corticosteroids are the preeminent antiinflammatory agents although the molecular mechanisms that impart their efficacy have not been defined. The endothelium plays a critical role in inflammation by directing circulating leukocytes into extravascular tissues by expressing adhesive molecules for leukocytes [e.g., endothelial-leukocyte adhesion molecule 1 (ELAM-1) and intercellular adhesion molecule 1 (ICAM-1)]. We therefore determined whether corticosteroids suppress inflammation by inhibiting endothelial expression of adhesion molecules for neutrophils (polymorphonuclear leukocytes). Preincubation of endothelial cells with endotoxin [lipopolysaccharide (LPS), 1 microgram/ml] led to a 4-fold increase in subsequent adherence of polymorphonuclear leukocytes (P < 0.0001, n = 10) to endothelial cells, an increase that was markedly attenuated when endothelial cells were treated with dexamethasone (IC50 < 1 nM, P < 0.0001, n = 6 or 7) during preincubation with LPS. Moreover, the steroid receptor agonist cortisol (10 microM), but not its inactive metabolite tetrahydrocortisol (10 microM), diminished LPS-induced endothelial cell adhesiveness. Further evidence that the action of dexamethasone was mediated through ligation of corticosteroid receptors [human glucocorticoid receptors (hGRs)] was provided by experiments utilizing the steroid antagonist RU-486. RU-486 (10 microM), which prevents translocation of ligated hGR to the nucleus by inhibiting dissociation of hGR from heat shock protein 90, completely aborted the effect of dexamethasone on adhesiveness of endothelial cells (P < 0.0005, n = 3). Treatment of endothelial cells with LPS (1 microgram/ml) stimulated transcription of ELAM-1, as shown by Northern blot analysis, and expression of membrane-associated ELAM-1 and ICAM-1, as shown by quantitative immunofluorescence (both P < 0.001, n = 9). Dexamethasone markedly inhibited LPS-stimulated accumulation of mRNA for ELAM-1 and expression of ELAM-1 and ICAM-1 (IC50 < 10 nM, both P < 0.001, n = 4-9); inhibition of expression by dexamethasone was reversed by RU-486 (both P < 0.005, n = 4-6). As in the adhesion studies, cortisol but not tetrahydrocortisol inhibited expression of ELAM-1 and ICAM-1 (both P < 0.005, n = 3 or 4). In contrast, sodium salicylate (1 mM) inhibited neither adhesion nor expression of these adhesion molecules. These studies suggest that antagonism by dexamethasone of endotoxin-induced inflammation is a specific instance of the general biological principle that the glucocorticoid receptor is a hormone-dependent regulator of transcription.
 ...
PMID:A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. 127 85

The endogenous adrenocortical response to sepsis is critical for host survival. The in vivo interactions among the endogenous glucocorticoid response, the induction of cytokines, and host survival during endotoxemia were explored in this study by use of the glucocorticoid receptor antagonist RU 486. Male Lewis rats underwent sterile insertion of a right jugular venous catheter. After a 72-h recovery period, animals received a 50% lethal dose of Escherichia coli endotoxin (2.5 mg/kg) via the catheter after pretreatment for 30 min prior to lipopolysaccharide (LPS) treatment with (i) vehicle alone intravenously (i.v.) (-corticosterone [-Cort]/-RU 486/+LPS) (n = 10), (ii) the antiglucocorticoid RU 486 (10 mg/kg) i.v. (-Cort/+RU 486/+LPS) (n = 11), or (iii) RU 486 (10 mg/kg) i.v. in animals that had undergone subcutaneous implantation of a corticosterone pellet at the time of catheter insertion (+Cort/+RU 486/+LPS) (n = 10). Except in animals receiving corticosterone pretreatment, baseline plasma corticosterone levels were low in all groups. Plasma corticosterone levels increased significantly (P less than 0.001) above the baseline following LPS administration. Animals in the -Cort/+RU 486/+LPS-treated group exhibited significantly increased mortality (P less than 0.001), with only 9% of the animals surviving at 72 h, as well as significantly increased plasma interleukin-6 levels, compared with animals receiving the vehicle alone (-Cort/-RU 486/+LPS), which showed 50% mortality. Pretreatment with corticosterone and RU 486 (+Cort/+RU 486/+LPS) significantly (P less than 0.001) reversed the mortality observed with RU 486 pretreatment alone (-Cort/+RU 486/+LPS), with 70% of the animals surviving at 72 h, and significantly attenuated the peak plasma tumor necrosis factor and interleukin-6 responses to LPS, compared with those in the animals treated with vehicle alone. These data demonstrate that the blockade of glucocorticoid binding by RU 486 increases LPS-induced mortality. The reversal of this effect by the induction of hypercorticosteronemia prior to RU 486 and LPS exposure (+Cort/+RU 486/+LPS) improves survival and is further associated with significant attenuation of cytokine production. Therefore, these data suggest that the protective effect of the endogenous glucocorticoid response to acute endotoxemia may result from the down-regulation of a potentially lethal cytokine response.
 ...
PMID:In vivo effects of the antiglucocorticoid RU 486 on glucocorticoid and cytokine responses to Escherichia coli endotoxin. 161 34

Data presented here indicate that the immature B cells of murine bone marrow (BM) may be as sensitive to glucocorticoids (GC) as are immature thymocytes, since physiological levels of the steroids significantly inhibited the response of these cells to trinitrophenylated lipopolysaccharide (TNP-LPS) in short-term culture. The in vitro response of B cells of the marrow to TNP-LPS was reduced more than 50% by concentrations of corticosterone and cortisol analogous to that found in plasma during stress and trauma. The more potent synthetic GC, dexamethasone (DX), caused a 50-80% decrease in plaque-producing cells at concentrations of 10(-6) and 10(-8) M. The same pattern of inhibition was noticed regardless of whether DX was added 24 hr prior or up to 48 hr after addition of antigen to culture. However, no inhibition in the response of B cells was noted when DX was added 72-96 hr after stimulation of the cultures. These effects were found to be specific for GC since neither testosterone nor progesterone at physiological concentrations inhibited the response, while the glucocorticoid receptor antagonist RU 38486 provided protection. A greater than 80% reduction in the proportion of B cells present in the DX-treated cultures was noted after 5 days, corresponding to the 80% inhibition of plaque-forming cell production observed at that time. This reduction in B cells was rapid since almost 40% of the B220+ cells were depleted within 12 hr of DX addition. These data indicate that physiological levels of GC can readily inhibit the capacity of BM to respond to antigen by depleting the cultures of immature B cells.
 ...
PMID:Suppression of the antigenic response of murine bone marrow B cells by physiological concentrations of glucocorticoids. 176 99

Inflammatory mediators, such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) are secreted by fixed tissue macrophages and exhibit local autocrine and paracrine effects as well as distant endocrine effects. Human fetal Kupffer cells, the fixed tissue macrophages of the liver, may play a role as modulators of immune and endocrine function in early embryonic and fetal development. In the present study we isolated human fetal Kupffer cells to greater than 90% purity and prepared short term cultures to investigate the effect of glucocorticoids on the secretion of the cytokine TNF alpha. Fetal Kupffer cells secreted TNF alpha and IL-1 beta after culture with bacterial lipopolysaccharide (LPS), indicating that these cells express mature macrophage function. Cortisol and dexamethasone dramatically suppressed the LPS-stimulated secretion of TNF alpha by fetal Kupffer cells. The inhibitory effects of glucocorticoids appeared to be specific, since estrogen, progesterone, and testosterone had no effect on LPS stimulation of TNF alpha production. None of the steroids tested altered basal production or enhanced the LPS-stimulated production of TNF alpha by fetal Kupffer cells. The inhibition by glucocorticoids could be reversed by the addition of RU 486, indicating that this effect was mediated by the glucocorticoid receptor. These results demonstrate that human fetal macrophages demonstrate mature macrophage function in early gestation; they can be activated to produce TNF alpha by a well characterized modulator of cellular function (LPS) and suppressed by glucocorticoids.
 ...
PMID:Glucocorticoids inhibit lipopolysaccharide-induced production of tumor necrosis factor-alpha by human fetal Kupffer cells. 185 61

Inflammatory mediators such as interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) exhibit local autocrine and paracrine effects as well as distant systemic effects on target cells. Human Kupffer cells, the fixed tissue macrophages of the liver, may modulate immune and endocrine function in early fetal development. We purified and cultured human fetal Kupffer cells to investigate the production of the cytokine, IL-6. Fetal Kupffer cells treated with bacterial lipopolysaccharide (LPS) produced IL-6 in a dose-dependent fashion with maximal secretion (1000 pg per 10(6) cells) observed within 12 h using 10 micrograms of LPS/ml. Cortisol and dexamethasone, but not oestrogen, progesterone, or testosterone, dramatically suppressed the LPS-stimulated secretion of IL-6 by fetal Kupffer cells. None of the steroids tested altered basal production or enhanced the LPS-stimulated production of IL-6 by fetal Kupffer cells. The inhibition of glucocorticoids could be reversed by the addition of RU 486, indicating that this effect was mediated by the glucocorticoid receptor. These results demonstrate that the production of IL-6 by fetal hepatic macrophages can be activated by LPS and suppressed by glucocorticoids. These studies suggest that Kupffer cells express mature macrophage function in early gestation and would be capable of regulatory roles in the growth and development of the fetus.
 ...
PMID:Regulation of interleukin-6 production in human fetal Kupffer cells. 203 Nov 50

Implantation of a 75-mg morphine pellet in sham-adrenalectomized male C3H/HeN mice resulted in significant elevations of serum corticosterone levels within 6 h. Corticosterone levels remained elevated (3- to 4-fold) for 72 h and had returned to normal by 120 h postimplantation. Within 48 h of pellet implantation, morphine-pelleted mice exhibited marked reductions in spleen (35%) and thymus weight (56%) relative to values in placebo-pelleted controls. In addition, adrenal hypertrophy was observed in the morphine-pelleted shams (50% increase in adrenal weight relative to placebo. The magnitude of splenic and thymic atrophy was reduced by about 50% in adrenalectomized morphine-pelleted mice (17% and 22% reductions, respectively) compared to that in adrenalectomized mice implanted with placebo pellets. Lymphocyte proliferative responses to the T-cell mitogen Concanavalin-A and the B-cell mitogen bacterial lipopolysaccharide were also significantly reduced in the morphine-pelleted sham mice. Morphine-induced suppression of Concanavalin-A- or lipopolysaccharide-stimulated lymphocyte proliferation was absent in adrenalectomized mice. Effects similar to adrenalectomy (e.g. lessening of magnitude of morphine-induced suppression of lymphoid organ weight and lymphocyte proliferation) were found in morphine-pelleted mice given the glucocorticoid receptor antagonist RU-486 at a dose of 10 mg/kg, twice daily. These studies imply that morphine-induced immunosuppression is at least in part mediated by the increase in serum corticosterone levels after implantation of the morphine pellet.
 ...
PMID:Role of adrenal cortical activation in the immunosuppressive effects of chronic morphine treatment. 203 88

We have examined the effect of dexamethasone (DM) and cortisol on the production of interleukin (IL)6 from the murine macrophage cell line RAW264.9, human monocytes, human endothelial cells and the human fibroblast cell line FS4. In RAW264.9 cells DM in the concentration range 10(-9) M to 10(-6) M inhibited the lipopolysaccharide (LPS)-induced production of IL6 by 10% to 90%. Cortisol had a similar effect, but was about 25 times less potent than DM. Also, when 10(-6) M of DM was added to the cultures after addition of LPS, it completely inhibited the residual 24-h production of IL6. Corresponding to the effect on IL6 production, DM (10(-6) M) reduced the mRNA levels for IL6 in the RAW264.9 cells. The glucocorticoid analogue RU 486 competes with DM and cortisol for the glucocorticoid receptor and reversed the inhibitory effect of DM, demonstrating that DM exerts its effect via the glucocorticoid receptor. DM also had an inhibitory effect on LPS-stimulated IL6 production in freshly isolated human monocytes, and on IL 1-stimulated IL6 production in human endothelial cells and FS4 fibroblasts. These results demonstrate that DM via a receptor-mediated mechanism inhibits IL6 production at the transcriptional level, and this may contribute to the anti-inflammatory and immunosuppressive effect of glucocorticoids.
 ...
PMID:Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts. 225 84

The binding characteristics of partially purified glucocorticoid receptor complexes from hormone sensitive, non-differentiating BCL1 cells to sequentially deproteinized BCL1 chromatin-cellulose was investigated. [3H]Triamcinolone acetonide (TA)-receptor complexes were purified (approx. 30-fold) from DEAE-cellulose columns by salt elution which allowed receptor activation only in the absence of molybdate. Addition of 10 mM molybdate completely blocked salt activation. The binding pattern of the activated [3H]TA-receptor complexes to chromatin-cellulose extracted with 0-8 M guanidine hydrochloride revealed three regions of increased binding activity (acceptor sites), at 2, 5 and 7 M guanidine hydrochloride. Acceptor site binding was markedly reduced for chromatin extracted with 3, 6 and 8 M guanidine hydrochloride. Non-activated receptor complexes demonstrated very low binding to deproteinized chromatin. It was also shown that chromatin binding required glucocorticoid receptors and that free ligand or ligand bound to other proteins did not bind significantly to chromatin. In addition, binding of [3H]TA-receptor complexes to partially deproteinized chromatin was competable by unlabeled TA-receptor complexes. Scatchard analysis demonstrated that chromatin from non-differentiating BCL1 cells possesses multiple, high-affinity binding sites which differ in their affinity for the glucocorticoid receptor. Partially deproteinized chromatin from lipopolysaccharide-stimulated BCL1 cells demonstrated a different pattern of receptor binding, i.e., receptor binding was significantly greater to chromatin previously extracted with 6-8 M guanidine hydrochloride. These results suggest that differentiation alters the state of chromatin and the interaction of non-histone protein/DNA acceptor sites with glucocorticoid receptors. These alterations may play a role in the acquisition of hormone resistance.
 ...
PMID:Binding of [3H]triamcinolone acetonide-receptor complexes to chromatin from the B-cell leukemia line, BCL1. 387 35

The effects of glucocorticoids were studied in lipopolysaccharide (LPS)-stimulated splenic murine B-cell leukemia line one (BCL1) cells. At 24 hr, LPS caused a 3-fold increase in [3H]-thymidine incorporation compared to similarly cultured unstimulated cells. Triamcinolone acetonide (TA) and dexamethasone at a concentration of 10(-8) M reduced [3H]thymidine incorporation 80 and 53%, respectively, while estradiol at concentrations of 10(-10) to 10(-5) M had no effect. A 500-fold excess of cortexolone or progesterone blocked the response of 10(-8) M TA by 42 and 38%, respectively, indicating that the glucocorticoid response could be inhibited by antiglucocorticoids. The maximum rate of thymidine incorporation in LPS-stimulated cells occurred at 24 hr, a time at which 10(-5) M TA present in parallel cultures from the initiation of LPS stimulation showed a 79% reduction in [3H]thymidine incorporation. If TA was added at any time after the initiation of LPS stimulation, the degree of decrease in nucleotide incorporation was not as marked. Therefore, maximum TA effect in LPS-stimulated BCL1 cells occurred when TA was added to cultures at the onset of mitogen stimulation. We also measured glucocorticoid-specific receptor in whole cells both before LPS stimulation and in BCL1 cells incubated 24 hr in the presence of LPS. The equilibrium dissociation constant, the number of sites/cell, and the hormone specificity of the glucocorticoid receptor were similar prior to and at the peak of mitogen stimulation.
 ...
PMID:Glucocorticoid effects on lipopolysaccharide-stimulated murine B-cell leukemia line (BCL1) cells. 660 83

An enhanced formation of nitric oxide (NO) due to induction of a calcium-independent (inducible) NO synthase (iNOS) contributes importantly to the cardiovascular failure caused by bacterial endotoxin. Repeated challenges with small doses of endotoxin result in tolerance to both peripheral vascular failure and death caused by subsequent injection of a higher dose of endotoxin. Here we investigate whether tolerance to endotoxin is associated with a lack of induction of iNOS in vivo and whether endogenous glucocorticoids play a role in the development of endotoxin tolerance. In anesthetized rats, i.v. administration of Escherichia coli endotoxin [lipopolysaccharide (LPS); 2 mg.kg-1] resulted in a prolonged decrease in mean arterial blood pressure (MAP) and hyporeactivity to the contractile responses elicited by norepinephrine (NE; 10 nM) in aortic rings ex vivo. Hyporeactivity to NE was partially reversed by NG-nitro-L-arginine methyl ester (0.3 mM) in vitro, suggesting that an enhanced formation of NO contributes to this hyporeactivity. There was a substantial increase in the activity of iNOS in the lung 3 h after i.v. injection of LPS (0.2 +/- 0.1 to 6.6 +/- 0.6 pmol.mg-1.min-1; n = 5; P < 0.01). Rats injected i.p. with LPS (0.5 mg.kg-1) for 4 consecutive days became tolerant to an i.v. injection of LPS (2 mg.kg-1) in that both hypotension and vascular hyporeactivity to NE were significantly attenuated. Moreover, in these endotoxin-tolerant rats, the induction of iNOS by LPS in the lung was attenuated by 63% +/- 6%. Injection of LPS caused a 9-fold increase in plasma corticosterone (CCS) levels within 2 h and CCS levels remained significantly elevated 6 and 24 h after LPS. Animals rendered tolerant to endotoxin by administration of a low dose of LPS (0.5 mg.kg-1, i.p.) for 4 days still had a 6-fold increase in plasma CCS levels 24 h after the last injection of LPS. When endotoxin-tolerant rats were treated with the glucocorticoid receptor antagonist RU 486 (50 mg.kg-1, p.o. 3 h prior to LPS), there was a restoration of the effects of LPS (2 mg.kg-1, i.v.) in causing hypotension, vascular hyporeactivity to NE, and iNOS induction in the lung. However, in control rats RU 486 enhanced neither the decrease in MAP nor the induction of iNOS in response to LPS (2 mg.kg-1, i.v.). Thus, cardiovascular tolerance to endotoxin is accompanied and explained by reduced induction of iNOS in vivo due to the elevation of endogenous glucocorticoid levels.
 ...
PMID:Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. 750 16


1 2 3 4 5 6 7 8 9 10 Next >>