UNIPROT:P43026 - FACTA Search

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)

Trypanosoma brucei brucei (Tbb) infection is a model of chronic immune response associated with severe neurological disorders believed to lead to coma and death. We hypothesized that exaggerated production of proinflammatory molecules within the cental nervous system (CNS) may be involved in the etiology of the disease, i.e., African Tripanosomiasis. The purpose of the present study was therefore to verify the effects of the parasite Tbb on the genetic expression of the immediate-early gene c-fos (index of cellular activity), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), inhibitory factor kappa B alpha (IkappaBalpha, index of the nuclear factor kappaB activity, the transcription factor of numerous proinflammatory molecules), and inducible nitric oxide synthase (iNOS) in the mouse brain. Adult male BALB/c mice received a single intraperitoneal injection of lipopolysaccharide (LPS, used as positive control for these markers that are induced in a transient manner by the endotoxin), Tbb, or vehicle solution and were sacrificed at multiple times (1 hr to 7 days) following the injection. Acute and chronic models induced a robust expression of c-fos in numerous regions of the brain, including the circumventricular organs (CVOs) and different nuclei involved in autonomic control. Although the effect of LPS was rapid and transient, Tbb pathogen stimulated c-fos only within 5 to 7 days. The genes encoding TNF-alpha and IL-6 cytokines were expressed in the CVOs and choroid plexus 1 and 3 hr after LPS injection, whereas no convincing hybridization signal was detected in the brains of Tbb-infected mice at any time. IL-6 and iNOS-expressing cells were also found along large blood vessels of LPS-treated mice, while scattered small TNF-alpha-expressing cells were observed across the brain 12 and 24 hr after the endotoxin treatment. Tbb caused a low to moderate expression of iNOS and IkappaBalpha genes in perivascular cells, but this effect was apparent only several days following the parasite infection. Taken together, these data indicate that LPS and Tbb stimulate c-fos expression in similar nuclei involved in autonomic control, an event occurring within the first 3 hr after the LPS insult and only 5 days post-Tbb injection. The mRNAs encoding proinflammatory cytokines were, however, not detected in Tbb-infected brains, which may be explained by the Tbb variant (MiTat 1.5) that caused high parasitaemias and mortality within 5 to 7 days.
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PMID:Neuronal activity and transcription of proinflammatory cytokines, IkappaBalpha, and iNOS in the mouse brain during acute endotoxemia and chronic infection with Trypanosoma brucei brucei. 1046 51

Endotoxic lipopolysaccharide (LPS) is a proinflammatory agonist produced by gram-negative bacteria and a contributor to the majority of the 400,000 septic shock cases recorded annually in US hospitals. The primary target cells for LPS are monocytes and macrophages. Their response consists of massive production of proinflammatory cytokines, reactive oxygen- and nitrogen-intermediates, procoagulants, and cell adhesion molecules. In turn, expression of these LPS-responsive factors contributes to collapse of the circulatory system, to disseminated intravascular coagulation, and to a 30% mortality rate. A common intracellular mechanism responsible for the expression of septic shock genes in monocytes and macrophages involves the activation of NF-kappaB. This transcription factor is regulated by a family of structurally related inhibitors including IkappaBalpha, IkappaBbeta, and IkappaBepsilon, which trap NF-kappaB in the cytoplasm. In this report, the investigators show that LPS derived from different gram-negative bacteria activates cytokine-responsive IkappaB kinases containing catalytic subunits termed IKKalpha (IKK1) and IKKbeta (IKK2). The kinetics of IKKalpha and IKKbeta activation in LPS-stimulated human monocytic cells differ from that recorded on their stimulation with tumor necrosis factor-alpha, thereby implying a distinct activation mechanism. LPS-activated IKK complexes phosphorylate all 3 inhibitors of NF-kappaB: IkappaBalpha, IkappaBbeta, and IkappaBepsilon. Moreover, LPS activates IKKbeta preferentially, relative to IKKalpha. Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-kappaB signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock.
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PMID:IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. 1047 96

In the presence of a protein synthesis inhibitor, cycloheximide, tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1beta), or lipopolysaccharide (LPS) induces human umbilical vein endothelial cells (HUVECs) to undergo apoptosis, suggesting that constitutive or inducible cytoprotective pathways are required for cell survival. We studied the correlation between nuclear factor-kappaB (NF-kappaB) activation and cell death induced by TNF-alpha, IL-1beta, or LPS. Adenovirus-mediated overexpression of a dominant-negative IkappaBalpha (inhibitor of kappaB) mutant blocked NF-kappaB activation by gel shift assay and blocked induction of vascular cell adhesion molecule-1 protein by TNF-alpha, IL-1beta, and LPS, a NF-kappaB-dependent response. In cells overexpressing the IkappaBalpha mutant, TNF-alpha induced cell death, whereas IL-1beta or LPS did not. We conclude that cell survival following TNF-alpha stimulation is NF-kappaB-dependent but that a constitutive or inducible NF-kappaB-independent pathway(s) protects IL-1beta- or LPS-treated HUVECs from cell death.
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PMID:NF-kappaB activation is required for human endothelial survival during exposure to tumor necrosis factor-alpha but not to interleukin-1beta or lipopolysaccharide. 1049 54

1. Andalusol, ent-6alpha,8alpha,18-trihydroxy-13(16),14-labdadiene, is a naturally occurring diterpene, isolated from Sideritis foetens (Lamiaceae). This compound exhibited therapeutic activity when evaluated in in vivo models of paw and ear inflammation (Navarro et al., 1997: Z. Naturforsch., 52, 844-849). The pharmacological effects of this diterpene have been analysed on the activation of the macrophage cell line J774 with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). 2. Incubation of J774 macrophages with andalusol (0.1 - 100 microM) inhibited the synthesis of nitrite caused by LPS (1 microg ml-1) in concentration and time-dependent manners. The maximal inhibition was observed when andalusol was added 30 min before LPS stimulation and decreased progressively as the interval between andalusol and LPS challenge increased up to 14 h. 3. Incubation of J774 cells with LPS resulted in the expression of NOS-2 protein (130 kDa) as identified by Western blot analysis. The levels of this enzyme decreased significantly in the presence of andalusol (IC50=10.5 microM), suggesting that this diterpene inhibited NOS-2 expression. 4. Andalusol inhibited nuclear factor kappaB activation, a transcription factor necessary for NOS-2 expression in response to LPS and IFN-gamma. This compound also inhibited the degradation of IkappaBalpha favouring the retention of the inactive NF-kappaB complexes in the cytosol. 5. Related compounds to andalusol but lacking the polyol groups were less effective inhibiting NOS-2 expression in LPS-activated macrophages. The present findings provide a mechanism by which the anti-inflammatory properties of this diterpene could be mediated.
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PMID:Inhibition of NOS-2 expression in macrophages through the inactivation of NF-kappaB by andalusol. 1051 39

Members of the NF-kappaB/RelB family of transcription factors play important roles in the regulation of inflammatory and immune responses. RelB, a member of this family, has been characterized as a transcription activator and is involved in the constitutive NF-kappaB activity in lymphoid tissues. However, in a previous study we observed an overexpression of chemokines in RelB-deficient fibroblasts. Here we show that RelB is an important transcription suppressor in fibroblasts which limits the expression of proinflammatory mediators and may exert its function by modulating the stability of IkappaBalpha protein. Fibroblasts from relb(-/-) mice overexpress interleukin-1alpha (IL-1alpha), IL-1beta, and tumor necrosis factor alpha in response to lipopolysaccharide (LPS) stimulation. These cells have an augmented and prolonged LPS-inducible IKK activity and an accelerated degradation which results in a diminished level of IkappaBalpha protein, despite an upregulated IkappaBalpha mRNA expression. Consequently, NF-kappaB activity was augmented and postinduction repression of NF-kappaB activity was impaired in these cells. The increased kappaB-binding activity and cytokine overexpression was suppressed by introducing RelB cDNA or a dominant negative IkappaBalpha into relb(-/-) fibroblasts. Our findings suggest a novel transcription suppression function of RelB in fibroblasts.
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PMID:RelB modulation of IkappaBalpha stability as a mechanism of transcription suppression of interleukin-1alpha (IL-1alpha), IL-1beta, and tumor necrosis factor alpha in fibroblasts. 1052 57

Excessive nitric oxide (NO) generated by hepatic cells in response to lipopolysaccharide (LPS) and inflammatory substances (e.g., platelet-activating factor [PAF]) is a key contributor to the pathophysiological outcomes observed in the liver during sepsis. In rats subjected to liver-focused endotoxemia, inducible nitric oxide synthase (iNOS) levels in the intact liver were elevated by 6 hours; cell-specific expression of iNOS messenger RNA (mRNA) was Kupffer cells (KCs), endothelial cells, and hepatocytes. Elevated serum alanine transaminase (ALT) levels at 6 hours confirmed hepatic damage. Pretreatment of endotoxemic rats with PAF receptor antagonists BN 50739 or WEB 2170 reduced serum ALT and iNOS mRNA levels in the intact liver. Pretreatment of cultured KCs with BN 50739 or WEB 2170 inhibited both LPS and PAF-induced iNOS mRNA formation. In addition, LPS-induced iNOS protein levels in KCs pretreated with BN 50739 or WEB 2170 were decreased. Exposure of KCs to either LPS or PAF caused the translocation of the p65 subunit of nuclear factor kappa B (NF-kappaB) into the nucleus and this process was attenuated by BN 50739 and WEB 2170. There was concomitant inhibition of LPS-dependent degradation of the inhibitory protein IkappaBalpha and increase in intracellular Ca(2+) in KC treated with BN 50739 or WEB 2170. Also, in KCs, LPS was able to induce iNOS mRNA expression independent of CD14. This response was inhibited by pretreatment of KCs with either BN 50739 or WEB 2170. Our findings indicate that PAF receptor antagonists convey protection against hepatocellular injury accompanied by a decrease in nitric oxide (NO) formation in the livers of endotoxemic rats.
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PMID:Suppression of lipopolysaccharide-induced nitric oxide synthase expression by platelet-activating factor receptor antagonists in the rat liver and cultured rat Kupffer cells. 1053 42

Alcohol use is typically associated with impaired immunity and increased host susceptibility to infection, partially due to decreased inflammatory response. Acute ethanol exposure has been shown to down-regulate monocyte production of inflammatory cytokines. Activation of the pluripotent transcription factor NFkappaB is a pivotal step in the induction of inflammatory cytokines, chemokines and growth factors. Therefore, we hypothesized that alcohol may alter NFkappaB activation, thus providing a mechanism for the decreased inflammatory cytokine production by monocytes after acute alcohol treatment. We show here for the first time that alcohol inhibits lipopolysaccharide (LPS)-induced NFkappaB activation in human monocytes by decreasing DNA binding of the p65/p50 heterodimer as seen in electrophoretic mobility shift and supershift assays. We also demonstrate that alcohol prevents LPS-induced nuclear translocation of p65 and to a lesser extent that of the p50 subunits. NFkappaB activation is regulated via phosphorylation and proteolytic degradation of IkappaB. Thus, we investigated the effect of acute ethanol treatment on IkappaB in human monocytes. Alcohol did not prevent LPS-induced IkappaBalpha degradation but decreased the levels of phospho-specific IkappaBalpha (Ser32). Finally, for the first time we show that de novo protein synthesis is necessary to bring about the ethanol-mediated inhibition of LPS-induced NFkappaB activation. Consequently, these results suggest that physiologically relevant concentrations of alcohol interfere with NFkappaB activation and thereby may affect the regulation of NFkappaB-controlled gene activation.
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PMID:Inhibition of lipopolysaccharide-mediated NFkappaB activation by ethanol in human monocytes. 1054 82

The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) modulates inflammation by inhibiting production of proinflammatory cytokines. Using a plasmid vector encoding alpha-MSH, we examined whether autocrine alpha-MSH inhibits activation of the nuclear transcription factor NF-kappaB, a factor that is essential to expression of proinflammatory cytokines, in human glioma cells (A-172). Electrophoretic mobility shift assays of nuclear extracts demonstrated that NF-kappaB activation induced by lipopolysaccharide was inhibited in glioma cells transfected with alpha-MSH vector. Western blot analysis revealed that this inhibition was linked to preservation of expression of IkappaBalpha protein. Chloramphenicol acetyltransferase assay indicated that NF-kappaB-dependent reporter gene expression was suppressed in A-172 cells transfected with alpha-MSH vector. Finally, fluorescence staining confirmed that A-172 cells bear alpha-MSH receptors. The findings are consistent with the idea that, in central nervous system (CNS) inflammation, autocrine alpha-MSH exerts anti-inflammatory actions via modulation of NF-kappaB activation by preservation of IkappaBalpha protein. Based on this action of the peptide, it should be possible to treat neurodegenerative disease, stroke, encephalitis, trauma, and other CNS disorders that have an inflammatory component through gene therapy with alpha-MSH vector.
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PMID:Autocrine alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation in human glioma. 1056 96

Vascular smooth muscle cells (SMCs) are important targets for endothelium-derived nitric oxide (NO), but this production is attenuated in injured and diseased arteries and during aging. However, SMCs can produce NO themselves by expressing an inducible form of NO synthase (iNOS) under inflammatory conditions and in the repair process after arterial injury. We examined iNOS expression in SMCs derived from the aortic media of newborn, young adult, and old rats. Our results show that SMCs from newborn rats cannot produce significant amounts of NO on stimulation with interferon-gamma plus lipopolysaccharide or interleukin-1beta. In contrast, SMCs from old rats exhibit markedly enhanced iNOS activity. The difference in iNOS activity between the newborn and the old SMCs was closely correlated with levels of iNOS protein, mRNA, and gene promoter activity. Similarly, intercellular adhesion molecule-1 (ICAM-1) was also expressed more abundantly in the old than in the newborn SMCs in response to cytokines. Both iNOS and ICAM-1 are transcriptionally regulated by nuclear factor kappaB (NF-kappaB). Our data demonstrate an intense transactivation of NF-kappaB in old SMCs on tumor necrosis factor-alpha stimulation but only a weak one in newborn SMCs. The difference in the NF-kappaB activation could be explained by a much faster and more extensive IkappaBalpha degradation in old than in newborn SMCs. These data indicate that the capability to respond to proinflammatory stimuli by activating NF-kappaB differs between SMCs at different stages of development. This results in differential capability to express NF-kappaB-dependent genes such as iNOS and ICAM-1, which could have implications for host defense and the pathogenesis of vascular diseases.
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PMID:Augmented expression of inducible NO synthase in vascular smooth muscle cells during aging is associated with enhanced NF-kappaB activation. 1059 61

When released into the bloodstream, proinflammatory cytokines have the ability to trigger the transcription of different genes in cells of the blood-brain barrier (BBB), including members of the nuclear factor kappa B (NF-kappaB) family and cyclooxygenase-2 (COX-2), the limiting enzyme for the formation of prostaglandins (PGs). The present study investigated the possibility that interleukin-1beta (IL-1beta) plays an essential role in these events during a systemic inflammatory response. Both wild-type and IL-1beta-deficient mice were killed at different times after two different immunogenic stimuli, i.e., intraperitoneal lipopolysaccharide (LPS) injection and intramuscular turpentine injection, used here as a model of systemic localized inflammatory insult. The inhibitory factor kappaBalpha (IkappaBalpha, index of NF-kappaB activity) and COX-2 transcripts were detected throughout the brain by means of in situ hybridization. Systemic LPS injection caused a strong and rapid expression of IkappaBalpha in endothelial cells lining the BBB of large and small blood vessels and thereafter within parenchymal microglia across the brain. This treatment also provoked a transient expression of COX-2 along cells of the vascular system, and the expression pattern and intensity of the signal for both transcripts were essentially the same in wild-type and IL-1beta-deficient animals. In contrast, the induction of these genes that was quite selective to the cells of the BBB in response to intramuscularly turpentine insult was completely abolished in IL-1beta-deficient mice. Indeed, a late and prolonged expression of IkappaBalpha and COX-2 mRNAs was found along the cerebral blood vessels in response to the sterile and localized inflammation in wild-type mice, whereas such induction was absent in the brain of IL-1beta-deficient animals. These results indicate that IL-1beta has an obligatory role in the activation of NF-kappaB molecules and PGs within endothelial cells of the BBB in an experimental model of intramuscularly turpentine-induced inflammation but not during endotoxemia.
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PMID:An essential role of interleukin-1beta in mediating NF-kappaB activity and COX-2 transcription in cells of the blood-brain barrier in response to a systemic and localized inflammation but not during endotoxemia. 1059 73

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