Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Estrogen's action on bone may be mediated by cytokines produced by monocytes. We have reported a decreased ratio of interleukin-1beta (IL-1beta) to interleukin-1 receptor antagonist (IL-1ra) produced by whole blood cultures in vivo in women taking hormone replacement therapy (HRT). Also, one study has shown an effect of estradiol on tumor necrosis factor-alpha (TNF-alpha) secretion by separated monocytes in vitro. The aim of this study was to evaluate the effect of estrogen in vitro on the secretion of cytokines using whole blood cultures. Subjects consisted of 12 healthy postmenopausal women, ages 57-69 years, 4-20 years since menopause. Cytokines IL-1beta, interleukin-1alpha (IL-1alpha), IL-1ra, interleukin-6 (IL-6), TNF-alpha, and granulocyte macrophage-colony stimulating factor (GM-CSF) were measured in unstimulated and in stimulated (500 ng/mL lipopolysaccharide [LPS]) whole blood cultures treated with 17beta-estradiol (E(2)) at concentrations of 10(-12)--10(-6) mol/L. We found significant decreases in the spontaneous secretion of IL-6, TNF-alpha, IL-1ra, IL-1beta, and ratio of IL-1beta/IL-1ra compared with control, at physiological concentrations of E(2). The action of E(2) was blocked by the use of the antiestrogen ICI 182780 in coculture. A decrease in cytokine secretion was not observed when the inactive form of estrogen, 17alpha-estradiol, was used in place of 17beta-estradiol. GM-CSF and IL-1alpha were not detectable in unstimulated cultures. Cytokine levels measured in stimulated cultures were not attenuated by treatment with E(2). We conclude that E(2) inhibits the spontaneous secretion of cytokines measured in whole blood cultures at physiological concentrations, and that the powerful stimulatory effect of LPS prevents any significant inhibition by E(2) in stimulated cultures.
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PMID:The effect of 17beta-estradiol on production of cytokines in cultures of peripheral blood. 1147 88

Estrogens have been suggested to modulate several inflammatory processes. Here, we show that IL-1beta treatment induced the expression of approximately 75 genes in the liver of ovariectomized mice. 17alpha-Ethinyl estradiol (EE) pretreatment reduced the IL-1beta induction of approximately one third of these genes. Estrogen receptor alpha (ERalpha) was required for this inhibitory activity, because EE inhibition of IL-1beta-stimulated gene expression occurred in ERbeta knockout mice, but not in ERalpha knockout mice. EE treatment induced expression of 40 genes, including the transcriptional repressor short heterodimer partner and prostaglandin D synthase, known modulators of nuclear factor-kappaB signaling. However, the ER agonists genistein and raloxifene both inhibited IL-1beta gene induction without stimulating the expression of prostaglandin D synthase, short heterodimer partner, or other ER-inducible genes, indicating that induction of gene expression was not required for ER inhibition of IL-1beta signaling. Finally, the ability of EE to repress IL-1beta gene induction varied among tissues. For example, EE inhibited IL-1beta induction of lipopolysaccharide-induced c-x-c chemokine (LIX) in the liver, but not in the spleen or lung. The degree of EE repression did not correlate with ER expression. cAMP response element binding protein-binding protein (CBP)/p300 levels also varied between tissues. Together, these results are consistent with a model of in vivo ER interference with IL-1beta signaling through a coactivator-based mechanism.
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PMID:Estrogen receptor alpha inhibits IL-1beta induction of gene expression in the mouse liver. 1207 88

The objective of this study was to explore whether and how ovarian hormones interact with the febrile response to pyrogens. Estrogen and progesterone treatment of ovariectomized rats was associated with a reduction in lipopolysaccharide (LPS)-induced fever, compared with ovariectomized controls. LPS-fever reduction was accompanied by reduced levels of the inducible cyclooxygenase-2 (COX-2) protein expression in the hypothalamus as well as reduced plasma levels of IL-1beta. The amount of LPS-induced IL-6 in the plasma was not affected by ovarian hormone replacement. In contrast, hypothalamic COX-2 expression in response to intraperitoneal injection of IL-1beta was potentiated by the ovarian hormone replacement. IL-1beta induced a moderate increase in plasma levels of IL-6 that was suppressed by ovarian hormone replacement. These data suggest that ovarian hormone replacement attenuated the proinflammatory response to LPS by suppressing the LPS-induced IL-1beta production and COX-2 expression in the hypothalamus. The markedly different action of ovarian hormones on IL-1beta and LPS effects suggests that this sex hormone modulation of the immune response is a function of the nature of infection and provides further evidence that LPS actions are different from those of IL-1beta.
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PMID:Neuroimmune response to endogenous and exogenous pyrogens is differently modulated by sex steroids. 1274 7

Estrogen is an immunoregulatory agent, in that hormone deprivation increases while 17beta-estradiol (E2) administration blocks the inflammatory response; however, the underlying mechanism is still unknown. The transcription factor p65/relA, a member of the nuclear factor kappaB (NF-kappaB) family, plays a major role in inflammation and drives the expression of proinflammatory mediators. Here we report a novel mechanism of action of E2 in inflammation. We observe that in macrophages E2 blocks lipopolysaccharide-induced DNA binding and transcriptional activity of p65 by preventing its nuclear translocation. This effect is selectively activated in macrophages to prevent p65 activation by inflammatory agents and extends to other members of the NF-kappaB family, including c-Rel and p50. We observe that E2 activates a rapid and persistent response that involves the activation of phosphatidylinositol 3-kinase, without requiring de novo protein synthesis or modifying Ikappa-Balpha degradation and mitogen-activated protein kinase activation. Using a time course experiment and the microtubule-disrupting agent nocodazole, we observe that the hormone inhibits p65 intracellular transport to the nucleus. This activity is selectively mediated by estrogen receptor alpha (ERalpha) and not ERbeta and is not shared by conventional anti-inflammatory drugs. These results unravel a novel and unique mechanism for E2 anti-inflammatory activity, which may be useful for identifying more selective ligands for the prevention of the inflammatory response.
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PMID:17beta-estradiol inhibits inflammatory gene expression by controlling NF-kappaB intracellular localization. 1579 85

Estrogen provides neuroprotection against neurodegenerative diseases, including Parkinson's disease. Its effects may stem from interactions with neurons, astrocytes, and microglia. We demonstrate here in primary cultures of rat mesencephalic neurons that estrogen protects them from injury induced by conditioned medium obtained from lipopolysaccharide (LPS)-activated microglia. LPS-induced nitrite production and tumor necrosis factor-alpha up-regulation in microglia were blocked by estrogen pretreatment. Estrogen neuroprotection was related to microglial activation of estrogen receptors (ERs), insofar as the protective effect of the microglia-conditioned medium was overridden by pretreatment of microglia with the ER antagonist ICI 182,780. On the other hand, the specific ERalpha antagonist, MPP dihydrochloride, only partially blocked the effects of estrogen, suggesting that estrogen protection was mediated via both ERalpha and ERbeta. LPS treatment did not change ERalpha mRNA levels in microglia, astrocytes, and neurons, but it up-regulated ERbeta mRNA levels in microglia and astrocytes. Similarly, increased ERbeta protein levels were detected in LPS-activated microglia. More interesting was that immunocytochemical analysis revealed that ERbeta was localized in the cytoplasm of microglia and in the cell nucleus of astrocytes and neurons. In summary, our results support the notion that estrogen inhibits microglial activation and thus exhibits neuroprotective effects through both ERalpha and ERbeta activation. The cytoplasm location of microglial ERbeta suggests the possible involvement of nonclassical effects of estrogen on microglia. Changes in microglial ERbeta expression levels may modulate such effects of estrogen.
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PMID:Estrogen provides neuroprotection against activated microglia-induced dopaminergic neuronal injury through both estrogen receptor-alpha and estrogen receptor-beta in microglia. 1601 43

The effects of estrogen therapy can differ depending on the regimen of estrogen administration. In addition, estrogen can modulate the effects of stressors. To examine the interaction between these systems, we infused adult female rats with lipopolysaccharide (LPS) into the fourth ventricle of the brain for 6 d and compared the effects of constant and pulsed estrogen replacement. Constant, but not pulsed, estrogen treatment reduced estrogen receptor-alpha (ERalpha) protein by 90% in the uterus and increased heat-shock proteins 70 and 90 by 74 and 48%, respectively, whereas progesterone receptor levels increased in all ovariectomized rats receiving estrogen replacement. In contrast to the uterine decline in ERalpha, no changes in ERalpha were observed in the hypothalamus or hippocampus, and ERbeta levels were unchanged in all regions tested. Brain infusion of LPS did not alter these proteins but increased the number of activated microglia in the thalamus and reduced body weight in all rats as well as activated the hypothalamic-pituitary-adrenal axis in ovariectomized rats, as determined by elevations in circulating corticosterone and progesterone. Estrogen treatments did not alter these markers, and no differences were observed in cortical choline acetyltransferase activity or nitrotyrosine for any of the treatment groups. The current study found an unexpected increase in uterine weight in lipopolysaccharide-infused rats treated with constant, but not pulsed, estrogen. This report suggests that constant and pulsed regimens of estrogen administration produce different effects and that stress may be an important factor in the postmenopausal intervention with estrogen.
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PMID:Brain infusion of lipopolysaccharide increases uterine growth as a function of estrogen replacement regimen: suppression of uterine estrogen receptor-alpha by constant, but not pulsed, estrogen replacement. 1702 24

Estrogen has been shown to attenuate the inflammatory response following injury or lipopolysaccharide treatment in several organ systems. Estrogen's actions are transduced through two estrogen receptor sub-types, estrogen receptor (ER) -alpha and estrogen receptor-beta, whose actions may be overlapping or independent of each other. The present study examined the effects of ERalpha- and ERbeta-specific ligands in regulating the inflammatory response in primary astrocyte cultures. Pre-treatment with 17beta-estradiol (ERalpha/ERbeta agonist), HPTE (ERalpha agonist/ERbeta antagonist) and DPN (ERbeta agonist) led to attenuation of IL-1beta, TNFalpha, and MMP-9 in astrocyte media derived from young adult (3-4 mos.) and reproductive senescent female (9-11 mos., acyclic) astrocyte cultures, while pretreatment with PPT (ERalpha agonist) attenuated IL-1beta (but not MMP-9) in both young and senescent-derived astrocyte cultures. Our previous work determined that 17beta-estradiol was unable to attenuate the LPS-induced increase in IL-1beta in olfactory bulb primary microglial cultures derived from either young adult or reproductive senescent females. In young adult-derived microglial cultures, the LPS-induced increase in IL-1beta was not attenuated by pre-treatment with 17beta-estradiol, PPT or HPTE. Interestingly, the ERbeta agonist, DPN significantly decreased IL-1beta following LPS treatment in young adult-derived microglia. Thus while both microglia and astrocytes synthesize and release inflammatory mediators, the present data shows that compounds which bind ERbeta are more effective in attenuating proinflammatory cytokines in both cell types and may therefore be a more effective agent for future therapeutic use.
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PMID:Effects of estrogen receptor agonists on regulation of the inflammatory response in astrocytes from young adult and middle-aged female rats. 1832 72

Atherosclerosis is an inflammatory disease where lipopolysaccharide (LPS) triggers the release of inflammatory cytokines that accelerate its initiation and progression. Estrogen has been proven to be vasoprotective against atherosclerosis; however, the anti-inflammatory function of estrogen in the vascular system remains obscure. In this study, we investigated the effect of estrogen on LPS-induced monocyte chemoattractant protein-1 (MCP-1; listed as CCL2 in the MGI database) production in vascular smooth muscle cells (VSMCs). LPS significantly enhances MCP-1 production and this is dependent on nuclear factor kappa B (NFkappaB) signaling, since the use of NFkappaB inhibitor pyrrolidine dithiocarbamate or the silencing of NFkappaB subunit p65 expression with specific siRNA largely impairs LPS-enhanced MCP-1 production. On the contrary, 17beta-estradiol (E(2)) inhibits LPS-induced MCP-1 production in a time- and dose-dependent manner, which is related to the suppression of p65 translocation to nucleus. Furthermore, p38 MAPK is rapidly activated in response to LPS, while E(2) markedly inhibits p38 MAPK activation. Transfection with p38 MAPK siRNA or the use of p38 MAPK inhibitor SB203580 markedly attenuates LPS-stimulated p65 translocation to nucleus and MCP-1 production, suggesting that E(2) suppresses NFkappaB signaling by the inactivation of p38 MAPK signaling. LPS promotes VSMCs migration and this is abrogated by MCP-1 antibody, implying that MCP-1 may play a major role as an autocrine factor in atherosclerosis. In addition, E(2) inhibits LPS-promoted cell migration by downregulation of MCP-1 production. Overall, our results demonstrate that E(2) exerts anti-inflammatory property antagonistic to LPS in VSMCs by reducing MCP-1 production, and this effect is related to the inhibition of p38 MAPK/NFkappaB cascade.
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PMID:17beta-estradiol down-regulates lipopolysaccharide-induced MCP-1 production and cell migration in vascular smooth muscle cells. 2053 89

Since estrogen and selective estrogen receptor modulators can inhibit inflammatory responses, we studied the regulatory role of several selective estrogen receptor modulators on interleukin-6 (IL-6) expression in human retinal pigment epithelial cells (ARPE-19). ARPE-19 cells were exposed to lipopolysaccharide with simultaneous exposure to different selective estrogen receptor modulators with the secretion of IL-6 cytokine being analyzed by enzyme-linked immunosorbent assay (ELISA). We demonstrate that 17beta-estradiol and HM-D, a novel selective estrogen receptor modulator compound, clearly reduced the IL-6 expression levels after lipopolysaccharide exposure in ARPE-19 cells. Molecular effects of selective estrogen receptor modulators and estrogen on the estrogen response element-mediated transcription were studied using MCF-7 and ARPE-19 cell lines carrying the estrogen response element-luciferase reporter gene. Estrogen and HM-D stimulated the activity of estrogen response element-reporter gene in MCF-7 cells but did not affect the activity in ARPE-19 cells. In addition, HM-D did not activate estrogen receptor alpha when studied by nuclear receptor peptide estrogen receptor alpha ELISA in ARPE-19 cells. These results indicate that estrogen and HM-D can suppress the lipopolysaccharide-induced inflammatory response but signalling is not mediated through estrogen response element transcription in human retinal pigment epithelial cells.
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PMID:Influence of selective estrogen receptor modulators on interleukin-6 expression in human retinal pigment epithelial cells (ARPE-19). 2054 20

Mucins play an essential role as mucosal barrier to prevent invasion of pathogens in the oviductal tissue of hens. The aim of this study was to determine the effect of estradiol and lipopolysaccharide (LPS) on the mucin expression in the lower oviductal segments (vagina and uterus) of hens. The mucosal tissues of the vagina and uterus were collected from White Leghorn laying and molting hens, and molting hens with or without intramuscular injection with 1 mg of estradiol-benzoate (EB) daily for 7 d. Part of these tissues was cultured in TCM-199 culture medium with or without LPS (10, 100, or 1,000 ng/mL) for 1.5 or 3 h. Mucin expression in the mucosa of laying, molting, and EB-treated molting hens (EB-group) and in those tissues cultured with or without LPS was analyzed by quantitative reverse-transcription PCR. Cultured tissues were also processed for paraffin sections and stained with Alcian blue (AB). In both the vagina and uterus, mucin expression and density of AB-positive mucopolysaccharide were reduced in molting hens compared with laying hens, and upregulated by EB. Mucin expression in the cultured vagina and uterus tissues of laying and molting hens was upregulated by LPS in a dose- and time-dependent manner. However, there was no response to LPS for induction of mucin in the tissues of EB-group hens. The mucin expression level in the vagina and uterus tissues stimulated by LPS was lower in the EB-group hens than in laying and molting hens, and that in the uterus was lower in the molting hens than in laying hens. These results suggest that mucin expression is stimulated by LPS in the vagina and uterus of laying and molting hens. Estrogen may upregulate mucin expression in those tissues in association with epithelial development, whereas it may suppress the response to LPS for mucin induction. The mucin expression caused by LPS may enhance mucosal barrier function and play a role in preventing infections by bacteria in the vagina and uterus.
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PMID:Induction of mucin expression by estrogen and lipopolysaccharide in the lower oviductal segments in hens. 2423 31


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