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)

The thiol reducing agent N-acetylcysteine (NAC) is commonly used as an "antioxidant" in studies examining gene expression, signaling pathways, and outcome in acute and chronic models of lung injury. It is less widely appreciated that NAC can also undergo auto-oxidation and behave as an oxidant. We showed previously that NAC can have opposite effects on the activation of nuclear factor-kappaB depending on whether or not serum is present, and that the effects of NAC in the absence of serum are mimicked by various oxidants. Here we show that in a serum-depleted environment (0.1% fetal bovine serum), NAC substantially inhibited lipopolysaccharide (LPS) activation of the mitogen-activated protein kinases (MAPKs), namely extracellular signal-regulated kinase (ERK), p38mapk, and c-Jun NH2-terminal kinase (JNK). By contrast, in the presence of 10% serum, NAC had no effect on LPS activation of p42 and p44 ERK and in fact enhanced LPS induction of p38mapk and JNK phosphorylation. Because serum can significantly alter the redox state, these findings highlight the importance of the local redox milieu in signal transduction.
 ...
PMID:Redox paradox: effect of N-acetylcysteine and serum on oxidation reduction-sensitive mitogen-activated protein kinase signaling pathways. 1135 Aug 34

Oxidative stress appears to be one of the primary factors contributing to an age related decline in steroidogenic response in rat adrenocortical and testicular Leydig cells. In this report we concentrate on age-related changes in the DNA binding activity of the transcription factor AP-1 which is particularly responsive to changes in cellular oxidative conditions: adrenal nuclear extracts from young mature (5 months) and old (24 months) rats treated with, and without, lipopolysaccharide (LPS) were studied. AP-1 binding activity, as measured by electrophoretic mobility shift assays (EMSA), was diminished approximately 70% with age in unstimulated adrenals. Following LPS treatment, AP-1 binding activity increased significantly in the adrenals of both young and old animals; however, the level of AP-1 binding achieved in LPS-stimulated old rats was less than that observed for LPS-stimulated young rats. There was no corresponding change in the binding activity of housekeeping transcription factors SP-1 and OCT-1. To further understand these observations, compositional changes in the members of the AP-1 DNA-binding complex were examined by a super-shift assay and Western blot analysis. In adrenals from old rats, a significant decrease in the amount of Fra2 was noted under basal conditions, whereas, substantial decreases in c-Fos, Jun D and c-Jun were observed in response to LPS treatment. In contrast, basal levels of JunB, an inhibitor of the trans-activating function of c-Jun and repressor of AP-1-dependent transcription, were significantly elevated in adrenals from old rats compared to young rats. Together, these findings suggest that ageing-induced oxidative stress may contribute to impaired functional expression of AP-1 by differentially regulating the steady state levels of AP-1 components. The observed decrease in AP-1 binding activity in ageing adrenals is most likely due to decreased expression of the AP-1 activating components (c-Fos, c-Jun, JunD, etc.) and increased expression of JunB, resulting in a switch from transcriptionally active AP-1 complexes observed in young rats to less efficient JunB containing complexes in old rats.
 ...
PMID:Impaired activation of AP-1 and altered expression of constituent proteins in rat adrenal during ageing. 1138 31

The bradykinin B1 receptor (BKB1R) gene is expressed in selected tissues such as lung and kidney. In these tissues it is expressed at a very low level until induced by inflammatory mediators. Our aim has been to understand the mechanism of this regulatory process. A human BKB1R minigene was constructed. It contained a 1.8 kb promoter, the entire exon I, 1.5 kb of intron I, the entire exon II and intron II, and the luciferase gene as a reporter. Transient transfection of the minigene into SV40-transformed IMR90 cells (IMRSV) resulted in a promoter activity which was activated by the mediators, lipopolysaccharide and (LPS) desArg(10)-kallidin. In contrast, these mediators did not induce the activity of the 1.8 kb promoter construct alone. Thus, motifs exclusive of the promoter such as 5'-UTR and/or intron regions are required for mediator-induced expression of this gene. Promoter activities of both the minigene and the 1.8 kb promoter construct were enhanced in a dose-dependent manner upon cotransfection with c-Jun. Furthermore, cotransfecting c-Jun with the minigene achieved the maximal promoter activity with no further increase in response to mediators. Conversely, the induction of the minigene promoter activity by mediators was abolished upon cotransfection with a dominant negative mutant of c-Jun. Other experiments suggest that multiple AP-1 sites are interactive with the c-Jun upregulation of this gene. Taken together, these results point to c-Jun as a key intermediary in the activation of the expression of this gene by mediators. However, participation of motifs outside of the promoter are necessary to obtain this inducible expression.
 ...
PMID:Mediator caused induction of a human bradykinin B1 receptor minigene: participation of c-Jun in the process. 1140 Jan 73

In this study, we examined the expression of nerve growth factor (NGF) and its receptors in mouse macrophages and the mechanisms involved in the effect of NGF on tumor necrosis factor (TNF)-alpha production. Macrophages expressed NGF and the NGF receptors TrkA and p75. Treatment of J744 cells or peritoneal macrophages with NGF induced a large increase in the production of TNF-alpha. In addition, NGF induced the secretion of nitric oxide in interferon-gamma-treated J774 cells or lipopolysaccharide-treated peritoneal macrophages. The induction of TNF-alpha production by NGF was blocked by K252a, an inhibitor of the TrkA receptor. NGF induced phosphorylation and activation of extracellular signal-regulated kinase, Erk1/Erk2 and c-Jun amino-terminal kinase, whereas it did not induce phosphorylation of p38 mitogen-activated protein kinase. Inhibition of the MAP kinase-Erk kinase pathway with PD 098059 decreased the secretion of TNF-alpha by NGF. Our results suggest that NGF has an important role in the activation of macrophages during inflammatory responses via activation of mitogen-activated protein kinases.
 ...
PMID:Nerve growth factor regulates TNF-alpha production in mouse macrophages via MAP kinase activation. 1140 90

The amiloride-inhibitable Na(+)/H(+) antiporter plays an important role in macrophage activation. The intracellular pathways leading to interleukin (IL)-12 p40 production by activated macrophages are incompletely understood. In the present study, we examined the contribution of the Na(+)/H(+) antiporter to the production of IL-12 p40. Amiloride or its analogs decreased the production of IL-12 p40 in macrophages stimulated with bacterial lipopolysaccharide and interferon-gamma. The order of potency of amiloride analogs was consistent with the proposition that the effect of amiloride is mediated by the inhibition of the Na(+)/H(+) antiporter. The effect of amiloride was post-transcriptional, as IL-12 p40 mRNA levels induced by lipopolysaccharide and interferon-gamma were not affected by this inhibitor. Furthermore, the inhibitory effect of amiloride on IL-12 p40 production was not a result of interference with the activation of the p38 and p42/44 mitogen-activated protein kinases or c-Jun kinase. In summary, the production of IL-12 p40 requires a functional Na(+)/H(+) antiporter.
 ...
PMID:Inhibition of the Na(+)/H(+) antiporter suppresses IL-12 p40 production by mouse macrophages. 1142 Jan 21

Helicobacter pylori lipopolysaccharide (LPS) is generally accepted as a low-toxicity virulence. Primary cultures of guinea pig gastric mucosal cells expressed the Toll-like receptor 4 and were sensitive to H. pylori LPS as well as Escherichia coli LPS. H. pylori LPS stimulated phosphorylation of transforming growth factor-beta-activated kinase 1 (TAK1), TAK1-binding protein 1 (TAB1), and c-Jun NH(2)-terminal kinase (JNK) 2. H. pylori LPS at >2.1 endotoxin unit/ml (>1 ng/ml) activated caspase-8, stimulated cytochrome c release from mitochondria, and subsequently activated caspases-9 and -3, leading to apoptosis. Epidermal growth factor blocked all of these apoptotic processes and inhibited apoptosis, whereas it did not modify the phosphorylation of TAK1, TAB1, and JNK2. A comparatively specific inhibitor of caspase-8 or -9 blocked apoptosis, whereas cytochrome c release was prevented only with a caspase-8-like inhibitor. Our results suggest that caspase-8 and mitochondria may play crucial roles in H. pylori LPS-induced apoptosis and that this accelerated apoptosis may be involved in abnormal cell turnover of H. pylori-infected gastric mucosa.
 ...
PMID:Helicobacter pylori lipopolysaccharide induces apoptosis of cultured guinea pig gastric mucosal cells. 1151 85

The anti-inflammatory agent sulphasalazine is an important component of several treatment regimens in the therapy of ulcerative colitis, Crohn's disease and rheumatoid arthritis. Sulphasalazine has many immunomodulatory actions, including modulation of the function of a variety of cell types, such as lymphocytes, natural killer cells, epithelial cells and mast cells. However, the effect of this agent on macrophage (M phi) function has not been characterized in detail. In the present study, we investigated the effect of sulphasalazine and two related compounds - sulphapyridine and 5-aminosalicylic acid - on M phi activation induced by bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). In J774 M phi stimulated with LPS (10 microg/ml) and IFN-gamma (100 U/ml), sulphasalazine (50-500 microM) suppressed nitric oxide (NO) production in a concentration-dependent manner. The expression of the inducible NO synthase (iNOS) was suppressed by sulphasalazine at 500 microM. Sulphasalazine inhibited the LPS/IFN-gamma-induced production of both interleukin-12 (IL-12) p40 and p70. The suppression of both NO and IL-12 production by sulphasalazine was superior to that by either sulphapyridine or 5-aminosalicylic acid. Although the combination of LPS and IFN-gamma induced a rapid expression of the active forms of p38 and p42/44 mitogen-activated protein kinases and c-Jun terminal kinase, sulphasalazine failed to interfere with the activation of any of these kinases. Finally, sulphasalazine suppressed the IFN-gamma-induced expression of major histocompatibility complex class II. These results demonstrate that the M phi is an important target of the immunosuppressive effect of sulphasalazine.
 ...
PMID:Sulphasalazine inhibits macrophage activation: inhibitory effects on inducible nitric oxide synthase expression, interleukin-12 production and major histocompatibility complex II expression. 1152 38

The lipopolysaccharide (LPS) receptor is a multi-protein complex that consists of at least three proteins, CD14, TLR4, and MD-2. Because each of these proteins is glycosylated, we have examined the functional role of N-linked carbohydrates of both MD-2 and TLR4. We demonstrate that MD-2 contains 2 N-glycosylated sites at positions Asn(26) and Asn(114), whereas the amino-terminal ectodomain of human TLR4 contains 9 N-linked glycosylation sites. Site-directed mutagenesis studies showed that cell surface expression of MD-2 did not depend on the presence of either N-linked site, whereas in contrast, TLR4 mutants carrying substitutions in Asn(526) or Asn(575) failed to be transported to the cell surface. Using a UV-activated derivative of Re595 LPS (ASD-Re595 LPS) in cross-linking assays, we demonstrated a critical role of MD-2 and TLR4 carbohydrates in LPS cross-linking to the LPS receptor. The ability of the various glycosylation mutants to support cell activation was also evaluated in transiently transfected HeLa cells. The double mutant of MD-2 failed to support LPS-induced activation of an interleukin-8 (IL-8) promoter-driven luciferase reporter to induce IL-8 secretion or to activate amino-terminal c-Jun kinase (JNK). Similar results were observed with TLR4 mutants lacking three or more N-linked glycosylation sites. Surprisingly, the reduction in activation resulting from expression of the Asn mutants of MD-2 and TLR4 can be partially reversed by co-expression with CD14. This suggests that the functional integrity of the LPS receptor depends both on the surface expression of at least three proteins, CD14, MD-2, and TLR4, and that N-linked sites of both MD-2 and TLR4 are essential in maintaining the functional integrity of this receptor.
 ...
PMID:MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor. 1170 42

Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 (K(i) = 0.19 microM). SP600125 is a reversible ATP-competitive inhibitor with >20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genes COX-2, IL-2, IFN-gamma, TNF-alpha, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-alpha and inhibited anti-CD3-induced apoptosis of CD4(+) CD8(+) thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
 ...
PMID:SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. 1171 29

The vital role of interferons (IFNs) as mediators of innate immunity is well established. It has recently become apparent that one of the pivotal proteins in mediating the antiviral activity of IFNs, the double-stranded RNA (dsRNA)-activated protein kinase (PKR), also functions as a signal transducer in the proinflammatory response to different agents. PKR is a member of a small family of kinases that are activated by extracellular stresses and that phosphorylate the alpha subunit of protein synthesis initiation factor eIF-2, thereby inhibiting protein synthesis. The activation of PKR during infection by viral dsRNA intermediates results in the inhibition of viral replication. PKR also mediates the activation of signal transduction pathways by proinflammatory stimuli, including bacterial lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha), and interleukin 1 (IL-1). PKR is a component of the inhibitor of kappaB (IkappaB) kinase complex and plays either a catalytic or structural role in the activation of IkappaB kinase, depending on the stimulus. The activities of the stress-activated protein kinases p38 and c-Jun NH(2)-terminal kinase (JNK) are also regulated by PKR in a pathway that leads to the production of proinflammatory cytokines. This review will focus on the role of PKR in nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways, because these have been the subjects of a series of publications over the past year that have reported conflicting findings. Although the conflicts may not be resolved in this review, suggestions are made for experiments that could lead to a clearer understanding of the mechanisms involved.
 ...
PMID:Signal integration via PKR. 1175 61


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