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)

To elucidate the mechanisms of immunostimulation by bacterial DNA and synthetic oligonucleotides, the effects of heat shock protein 90 (Hsp90) inhibitors on the activation of murine spleen cells and macrophages by these molecules were investigated. Murine spleen cells and J774 and RAW264.7 macrophages responded to a CpG-containing oligodeoxynucleotide (CpG ODN) and Escherichia coli DNA by increased production of interleukin 6 (IL-6), IL-12, tumor necrosis factor alpha, and nitric oxide (NO). Pretreatment with any of the three Hsp90 inhibitors geldanamycin, radicicol, and herbimycin A resulted in a dose-dependent suppression of cytokine production from the spleen cells and macrophages and of NO from macrophages stimulated with CpG ODN or E. coli DNA. These Hsp90 inhibitors, however, had no effect on Staphylococcus aureus Cowan strain 1-induced IL-12 production from either the murine spleen cells or macrophages. CpG ODN and E. coli DNA induced increased intracellular levels of phosphorylated extracellular signal-regulated kinases (ERK1 and -2), which are members of the mitogen-activated protein (MAP) kinase family, while geldanamycin and radicicol blocked the phosphorylation of ERK1 and -2 in J774 and RAW264.7 cells. These data indicate that DNA-induced activation of murine spleen cells and macrophages is mediated by Hsp90 and that Hsp90 inhibitor suppression of DNA-induced macrophage activation is associated with disruption of the MAP kinase signaling pathway. Our findings suggest that Hsp90 inhibitors may provide a useful means of elucidating the mechanisms of immunostimulation by bacterial DNA and CpG ODN as well as a strategy for preventing adverse effects of bacterial DNA as well as lipopolysaccharide.
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PMID:Role of the heat shock protein 90 in immune response stimulation by bacterial DNA and synthetic oligonucleotides. 1150 Apr 28

1. In rat aortic smooth muscle cells (RASMC), exposure to lipopolysaccharide (LPS) resulted in NF-kappaB-DNA binding, degradation of IkappaB-alpha, -beta and -epsilon and increased activity of both alpha and beta isoforms of inhibitory kappa B kinase (IKK). 2. Expression of dominant-negative (DN)-IKK-alpha, IKK-beta and NF-kappaB-inducing kinase (NIK) abolished LPS-stimulated NF-kappaB reporter activity, suggesting that activation of a NIK/IKK-dependent pathway is indispensable for NF-kappaB activation by LPS in this cell type. 3. The tyrosine phosphatase inhibitor, pervanadate, abolished LPS-stimulated NF-kappaB-DNA-binding activity. However, the effect of pervanadate was shown to be mediated by excess hydrogen peroxide (H(2)O(2)) present in the reaction mix. Preincubation of RASMC with H(2)O(2) inhibited LPS-stimulated IKK kinase activity and downstream NF-kappaB-DNA binding activity. 4. H(2)O(2) also strongly stimulated p38 MAP kinase activity in RASMCs. Effective inhibition of this pathway using SB203580 did not reverse the effects of H(2)O(2) on LPS-stimulated IKK/NF-kappaB signalling. 5. These studies show that hydrogen peroxide-mediated inhibition of LPS-stimulated NF-kappaB activation in RASMC occurs upstream of IKK. The inhibitory effect of H(2)O(2) is not due to tyrosine phosphatase inhibition, it is mediated by H(2)O(2) through a mechanism which is independent of any cross-talk involving MAP kinase homologues.
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PMID:Hydrogen peroxide-mediated inhibition of lipopolysaccharide-stimulated inhibitory kappa B kinase activity in rat aortic smooth muscle cells. 1156 58

Early events in the response of cells to lipopolysaccharide (LPS) include activation of NF-kappaB and stress-activated MAP kinase p38. Recent studies have shown that the human Toll-like receptor 2 (TLR2) mediates activation of NF-kappaB in response to commercial preparations of LPS (comLPS), membrane lipoproteins, and Gram-positive bacterial products. Here, we show that expression of TLR2 in human embryonic kidney 293 cells enabled p38 phosphorylation in response to comLPS, a synthetic bacterial lipoprotein, and B. subtilis. Activation of p38 was confirmed by an in vitro kinase assay using ATF2 as substrate and by an assay measuring activation of the downstream effector of p38, MAP kinase-activated protein kinase in cells. Thus, TLR2 initiated the signaling pathway for p38 in response to bacterial products.
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PMID:Toll-like receptor 2 (TLR2) mediates activation of stress-activated MAP kinase p38. 1186 88

The prostaglandin, 15-deoxy Delta(12,14)-prostaglandin J2 (15d-PGJ2)(1), and thiazolidinediones are ligands for the nuclear receptor, peroxisome proliferator-activated receptor (PPAR)-gamma, which mediates anti-inflammatory activity by suppressing murine macrophage (Mphi) production of the inflammatory mediator, nitric oxide (NO). Here, we elucidated this anti-inflammatory activity further by investigating whether PPAR-gamma ligands regulated a panel of proinflammatory and anti-inflammatory cytokines produced by primary inflammatory murine Mphi (thioglycollate-elicited peritoneal exudate Mphi; PEM). Thiazolidinediones and 15d-PGJ2 suppressed lipopolysaccharide (LPS)-induced PEM production of NO and IL-12(p40) to a greater extent than IL-6 and TNF-alpha production. Whereas 15d-PGJ2 showed the greatest extent of suppression of proinflammatory mediator production, the thiazolidinedione, BRL49653, was the most potent compound studied. Surprisingly, treatment with the Mphi-activation cytokine, IFN-gamma, prevented PPAR-gamma ligands from suppressing the proinflammatory cytokines completely and reduced their suppression of NO production substantially, demonstrating that activation conditions affect PPAR-gamma-mediated, anti-inflammatory activity. Western analysis demonstrated that the antagonistic activity of IFN-gamma did not involve modulation of PPAR-gamma expression but showed that IFN-gamma interfered with PPAR-gamma ligand regulation of p42/p44 MAP kinase activation and the cytosolic disappearance of NF-kappaB upon LPS stimulation. Finally, we showed that PPAR-gamma ligands did not substantially modulate production of the anti-inflammatory cytokine, IL-10, and that antibody-mediated neutralization of IL-10 did not prevent the ligands from suppressing proinflammatory mediator production. In contrast to studies with noninflammatory human monocytes and Mphi, our results demonstrate that primary murine inflammatory Mphi are extremely sensitive to the anti-inflammatory activity of PPAR-gamma ligands. These results suggest that drugs such as thiazolidinediones may be most effective in suppressing Mphi activity early (i.e., in the absence of lymphocyte-derived IFN-gamma) in the inflammatory process.
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PMID:Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-gamma: counter-regulatory activity by IFN-gamma. 1192 55

The liver is an important site of host-microbe interaction. Although hepatocytes have been reported to be responsive to lipopolysaccharide (LPS), the global gene expression changes by LPS and mechanism(s) by which LPS stimulates cultured hepatocytes remain uncertain. Cultures of primary mouse hepatocytes were incubated with LPS to assess its effects on the global gene expression, hepatic transcription factors, and mitogen-activated protein (MAP) kinase activation. DNA microarray analysis indicated that LPS modulates the selective expression of more than 80 genes and expressed sequence tags. We have shown previously that hepatocytes express CD14, which is required both for uptake and responsiveness to LPS. In other cells, responsiveness to microbial products requires expression of Toll-like receptors (TLR) and their associated accessory molecules. Hepatocytes expressed TLR1 through TLR9 as well as MyD88 and MD-2 transcripts, as shown by reverse transcriptase PCR analysis, indicating that hepatocytes express all known microbe recognition molecules. The MAP kinase extracellular signal-regulated kinase 1/2 was phosphorylated in response to LPS in mouse hepatocytes, and the levels of phosphorylation were lower in hepatocytes from TLR4-null mice. NF-kappa B activation was reduced in TLR4-mutant or -null hepatocytes compared to control hepatocytes, and this defect was partially restored by adenoviral transduction of mouse TLR4. Thus, hepatocytes respond to nanogram concentrations of LPS through a TLR4 response pathway.
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PMID:Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide. 1206 83

Exposure of macrophages to endotoxin [lipopolysaccharide (LPS)] results in a cascade of events resulting in the release of multiple inflammatory and anti-inflammatory mediators. The Toll-like receptor (TLR) 4 complex is the major receptor that mediates LPS signaling. However, there is evidence that other surface molecules may play a complementary role in the TLR-induced events. Integrin receptors are one class of receptors that have been linked to LPS signaling. This study investigates the role of macrophage integrin receptors in the activation of mitogen-activated protein (MAP) kinases by LPS. In conditions where macrophages were not permitted to adhere to matrix or a tissue culture surface, we found a decrease in LPS signaling as documented by a marked reduction in tyrosine phosphorylation of whole cell proteins. This was accompanied by a significant decrease in extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase MAP kinase activation. Inhibition of integrin signaling, with EDTA or RGD peptides, decreased LPS-induced MAP kinase activity. The functional consequence of blocking integrin signaling was demonstrated by decreased LPS-induced tumor necrosis factor-alpha production. These observations demonstrate that, in addition to the TLR receptor complex, optimal LPS signaling requires complementary signals from integrin receptors.
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PMID:Interaction of matrix with integrin receptors is required for optimal LPS-induced MAP kinase activation. 1211 1

In the central nervous system, glial cells play an important role in inflammatory and immune responses, and opioid peptides have been identified as essential mediators between the nervous and the immune systems. We report the profound upregulation of the opioid-related nociceptin/orphanin FQ (N/OFQ) by inflammatory mediators in astrocytes. The bacterial endotoxin, lipopolysaccharide (LPS), and the proinflammatory cytokines, interleukin-beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), induced levels of N/OFQ mRNA and immunoreactivity. HPLC analysis of the immunoreactivity in astrocyte extracts revealed that a large molecular weight precursor for N/OFQ is being synthesized and released in response to LPS and astrocytes appear to lack the enzymes required to process the precursor protein. Western blot analysis showed that LPS treatment elicited the activation of ERK 1/2 and p38 MAP kinases. Blockade of the p38 or the ERK MAP kinase pathways prevented the LPS-induced increase in N/OFQ mRNA levels indicating a role for these cascades in the regulation of N/OFQ genes in response to LPS. Regulation of N/OFQ gene expression by ERK and p38 activation may be mediated through the transcription factor CREB. We observed CREB phosphorylation in response to LPS, which was also prevented by SB202190 and PD98059. The NFkappaB pathway also appears to be involved in the induction of N/OFQ transcription by LPS, since NFkappaB inhibitors antagonized the effect of LPS on N/OFQ expression. Regulation of N/OFQ by inflammatory mediators in astrocytes may suggest a role for N/OFQ in neural-glial communication and in inflammatory responses in certain neuropathophysiological conditions.
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PMID:Inflammatory mediators increase the expression of nociceptin/orphanin FQ in rat astrocytes in culture. 1220 90

One of the immediate early microglial genes that are up-regulated in response to proinflammatory stimuli is cyclo-oxygenase 2 (COX-2). In the present study, we have investigated the effects of alpha-tocopherol (alpha TocH), an essential constituent of the nervous system, on the activation of COX-2 in lipopolysaccharide (LPS)-stimulated mouse BV-2 microglia. In unstimulated BV-2 cells, COX-2 mRNA and protein were almost undetectable but were strongly up-regulated in response to LPS. Activation of COX-2 protein synthesis in LPS-stimulated BV-2 cells involved activation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathway and was sensitive to the protein kinase C (PKC) inhibitors staurosporine and chelerythrine, and the MAP kinase/ERK kinase 1/2 inhibitors PD98059 and U0126. Supplementation of BV-2 cells with alpha TocH before LPS stimulation resulted in pronounced up-regulation of protein phosphatase 2A (PP2A) activity, down-regulation of PKC activity, ERK1/2 phosphorylation and nuclear factor kappa B (NF kappa B) activation. As a result, COX-2 protein levels and prostaglandin E(2) production were significantly lower in alpha TocH-supplemented cells. The effects of alpha TocH on PKC activity could be reverted by calyculin A and okadaic acid, two PP inhibitors. In summary, our results suggest that alpha TocH activates microglial PP2A activity and thereby silences an LPS-activated PKC/ERK/NF kappa B signalling cascade resulting in significantly attenuated COX-2 protein synthesis. These in vitro results imply that alpha TocH could induce quiescence to pathways that are associated with acute or chronic inflammatory conditions in the central nervous system.
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PMID:Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and synthesis in immortalized murine BV-2 microglia. 1242 20

Mitogen-activated protein (MAP) kinase and nuclear factor-kappaB (NF-kappaB) activation are critical for initiating the transcriptional expression of cytokines, cell adhesion molecules, and other factors in the macrophage immune response. Nitric oxide (NO), an endogenous free radical, is a product of macrophages that mediates inflammatory and cytotoxic processes in the immune system. Here we report the effects of NO on MAP kinase signaling and NF-kappaB activation in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and correlate these effects to the induction target genes, including interferon-beta (IFN-beta) and IkappaB-alpha. LPS alone induced a rapid phosphorylation of the stress-activated MAP kinases: c-Jun N-terminal kinase (JNK) and p38. Simultaneous treatment with LPS and the NO donor, diethylamine NONOate (DEA/NO), enhanced and prolonged JNK and p38 phosphorylation. Similarly, DEA/NO prolonged the LPS-induced degradation of the NF-kappaB inhibitory subunit, IkappaB-alpha, despite an increase in IkappaB-alpha mRNA levels. Whereas DEA/NO alone was sufficient to induce JNK and p38 phosphorylation, it was not sufficient to cause IkappaB-alpha degradation. The enhancement of IkappaB-alpha degradation by DEA/NO correlated with an increase in the nuclear levels of the p50 and p65 subunits and DNA-binding activity determined by electrophoretic mobility shift assay. DEA/NO and an additional NO donor, MAHMA/NO, are further demonstrated to enhance the transcriptional expression of the IFN-beta gene. The results suggest a role for NO in enhancing and propagating inflammatory conditions and the immune response.
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PMID:Nuclear factor-kappa B and mitogen-activated protein kinases mediate nitric oxide-enhanced transcriptional expression of interferon-beta. 1250 Sep 76

Adenylate/uridylate-rich element (ARE)-mediated mRNA turnover is an important regulatory component of gene expression for innate and specific immunity, in the hematopoietic system, in cellular growth regulation, and for many other cellular processes. This diversity is reflected in the distribution of AREs in the human genome, which we have established as a database of more than 900 ARE-containing genes that may utilize AREs as a means of controlling cellular mRNA levels. The p38 mitogen-activated protein kinase (MAP kinase) pathway has been implicated in regulating the stability of nine ARE-containing transcripts. Here we explored the entire spectrum of ARE-containing genes for p38-dependent regulation of ARE-mediated mRNA turnover with a custom cDNA array containing probes for 950 ARE mRNAs. The human monocytic cell line THP-1 treated with lipopolysaccharide (LPS) was used as a reproducible cellular model system that allowed us to precisely control the conditions of mRNA induction and decay in the absence and presence of the p38 inhibitor SB203580. This approach allowed us to establish an LPS-induced ARE mRNA expression profile in human monocytes and determine the half-lives of 470 AU-rich mRNAs. Most importantly, we identified 42 AU-rich genes, previously unrecognized, that show p38-dependent mRNA stabilization. In addition to a number of cytokines, several interesting novel AU-rich transcripts likely to play a role in macrophage activation by LPS exhibited p38-dependent transcript stabilization, including macrophage-specific colony-stimulating factor 1, carbonic anhydrase 2, Bcl2, Bcl2-like 2, and nuclear factor erythroid 2-like 2. Finally, the identification of the p38-dependent upstream activator MAP kinase kinase 6 as a member of this group identifies a positive feedback loop regulating macrophage signaling via p38 MAP kinase-dependent transcript stabilization.
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PMID:p38 Mitogen-activated protein kinase-dependent and -independent signaling of mRNA stability of AU-rich element-containing transcripts. 1250 43


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