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)

Macrophages are pivotal constituents of the innate immune system, vital for recognition and elimination of microbial pathogens. Macrophages use Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns--including bacterial cell wall components, such as lipopolysaccharide or lipoteichoic acid, and viral nucleic acids, such as double-stranded (ds)RNA--and in turn activate effector functions, including anti-apoptotic signalling pathways. Certain pathogens, however, such as Salmonella spp., Shigellae spp. and Yersiniae spp., use specialized virulence factors to overcome these protective responses and induce macrophage apoptosis. We found that the anthrax bacterium, Bacillus anthracis, selectively induces apoptosis of activated macrophages through its lethal toxin, which prevents activation of the anti-apoptotic p38 mitogen-activated protein kinase. We now demonstrate that macrophage apoptosis by three different bacterial pathogens depends on activation of TLR4. Dissection of anti- and pro-apoptotic signalling events triggered by TLR4 identified the dsRNA responsive protein kinase PKR as a critical mediator of pathogen-induced macrophage apoptosis. The pro-apoptotic actions of PKR are mediated both through inhibition of protein synthesis and activation of interferon response factor 3.
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PMID:The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. 1502

2-aminopurine (2-AP) is widely used as a specific inhibitor for double stranded-RNA dependent protein kinase (PKR). Here we report that 2-AP can inhibit lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production through the prevention of interferon (IFN)-beta production. 2-AP significantly inhibited NO production in LPS-stimulated RAW 264 murine macrophage cells. 2-AP also reduced the expression of IFN-beta and IFN-inducible genes, such as IFN-gamma-inducible protein (IP)-10 and immune-responsive gene (IRG)-1, and the inducible type of NO synthase (iNOS) mRNA in response to LPS. The addition of exogenous IFN-beta restored 2-AP-inhibited NO production in response to LPS. On the other hand, there was only partial inhibition by 2-AP of nuclear factor (NF)-kappaB activation, IL-6 mRNA expression and tumor necrosis factor (TNF)-alpha production. These results suggested that 2-AP inhibited LPS-induced IFN-beta production by preventing Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent signaling rather than myeloid differentiation factor (MyD) 88-dependent signaling, resulting in the inhibition of NO production.
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PMID:2-aminopurine inhibits lipopolysaccharide-induced nitric oxide production by preventing IFN-beta production. 1561 12

PKR, the double-stranded RNA (dsRNA)-activated serine/threonine kinase, has been implicated as an important component of host responses to infection and various situations of cellular stress. The involvement of PKR in signal transduction and regulation of transcription suggested to us that it may play an important role in lipopolysaccharide (LPS)-induced activation of STAT1 in rat brain immune cells. We found that LPS rapidly stimulated the phosphorylation of PKR within 5 min, followed by phosphorylation of STAT1 at 2 h in rat primary microglia and astrocyte. Using 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, and PKR-specific short interfering RNA (siRNA), we demonstrated that activation of PKR was essential for LPS-induced activation of STAT1. Inhibition of PKR activity by 2-AP resulted in suppression not only of STAT1 phosphorylation, but also of nuclear factors binding activity to GAS/ISRE elements. 2-AP also significantly suppressed the downstream events of LPS-stimulated STAT1 phosphorylation, including STAT-mediated transcriptional responses and generation of nitric oxide, a hallmark of brain inflammation. Consistent with these results, transfection of PKR-specific siRNA markedly attenuated all the STAT1 dependent inflammatory signaling responses tested. We further revealed that activation of PKR by LPS led to the induction of IFN-beta through activation of NF-kappaB, triggering the phosphorylation of STAT1 in rat brain glial cells. Taken together, these findings indicate that PKR functions as an essential modulator in LPS-induced STAT inflammatory signaling events, and provides new insight into endotoxin-induced CNS diseases following infection.
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PMID:Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells. 1563 Jul 3

1.--The small protein Bv8, isolated from the amphibian skin, belongs to a novel family of secreted proteins linked to several biological effects. We describe the expression of Bv8/prokineticins and their receptors in mouse macrophages, and characterize their proinflammatory activities. 2.--The rodent analogue of Bv8, prokineticin-2, is expressed by macrophages, as well as its G-protein-coupled receptor prokineticin receptor (PKR-1 and PKR-2). PKR-1 is expressed more abundantly. 3.-- Bv8 induces potent chemotaxis of macrophages at concentrations as low as 10(-12) M. 4.-- It stimulates lipopolysaccharide-induced production of the proinflammatory cytokines IL-1 and IL-12, reducing that of the anti-inflammatory cytokine IL-10. The effects are observed starting at the very low concentration of 10(-11) M. 5.--Effects on chemotaxis and cytokine are not pertussis-toxin sensitive, but are completely prevented by addition of the phospholipase inhibitor U73122, suggesting a G(q) protein is involved in the Bv8-induced effects. 6.--Studies in PKR-1 knockout mice indicate that all the activities exerted by Bv8 on macrophages are mediated by the PKR-1 receptor. 7.--In conclusion, Bv8 appears to be able to induce the macrophage to migrate and to acquire a proinflammatory phenotype.
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PMID:Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of mouse macrophages. 1629 50

The rainbow trout monocyte/macrophage-like cell line, RTS11, has been used to study homotypic aggregation (HA), which is a well-studied feature of leucocytes in mammals but less understood in fish. HA is the aggregation of cells of the same cell type. RTS11 underwent HA in response to polyinosinic:cytidylic acid (poly IC), polyadenylic acid (poly A), lipopolysaccharide (LPS), zymosan, and phorbol 12-myristate 13-acetate (PMA). Poly IC was the best inducer of HA and did so in a dose- and time-dependent manner. The induction of RTS11 aggregation by poly IC required divalent cations but was not blocked by either an inhibitor of lymphocyte function-associated molecule-1 (LFA-1) or the tripeptide integrin adhesion recognition sequence, RGD. Poly IC-induced HA was inhibited by colchicine and latrunculin B, which act on microtubules and microfilaments, respectively, implying the necessity for an intact cytoskeleton. HA induction by poly IC did not occur at 4 degrees C and was blocked by the transcriptional and translational inhibitors, actinomycin D and cycloheximide, respectively, suggesting the requirement for de novo protein synthesis. Poly IC-induced RTS11 aggregation was blocked by two inhibitors of dsRNA-dependent protein kinase (PKR). This is the first indication that PKR could have a role in the HA of leucocytes.
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PMID:Induction of homotypic aggregation in the rainbow trout macrophage-like cell line, RTS11. 1715 33

We previously developed a gene-gun-based in vivo screening system and identified shikonin as a potent suppressor of tumor necrosis factor-alpha (TNF-alpha) gene expression. Here, we show that shikonin selectively inhibits the expression of TNF-alpha at the RNA splicing level. Treatment of lipopolysaccharide-stimulated human primary monocytes and THP-1 cells with shikonin resulted in normal transcriptional induction of TNF-alpha, but unspliced pre-mRNA accumulated at the expense of functional mRNA. This effect occurred with noncytotoxic doses of shikonin and was highly specific, because mRNA production of neither a housekeeping gene nor another inflammatory cytokine gene, interleukin-8 (IL-8), was affected. Moreover, cotreatment with lipopolysaccharide (LPS) and shikonin increased the endpoint protein production of IL-8, accompanied by suppressed activation of the double-stranded RNA-activated protein kinase (PKR) pathway. Because PKR inactivation has been shown to down-regulate the splicing process of TNF-alpha RNA and interfere with translation, our findings suggest that shikonin may achieve differential modulation of cytokine protein expression through inactivation of the PKR pathway and reveal that regulation of TNF-alpha pre-mRNA splicing may constitute a promising target for future anti-inflammatory application.
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PMID:Inhibition of tumor necrosis factor-alpha through selective blockade of Pre-mRNA splicing by shikonin. 1736 Aug 31

Macrocyclic trichothecene mycotoxins produced by indoor air molds potentially contribute to symptoms associated with damp building illnesses. The purpose of this investigation was to determine (1) the kinetics of nasal inflammation and neurotoxicity after a single intranasal instillation of roridin A (RA), a representative macrocyclic trichothecene; and (2) the capacity of lipopolysaccharide (LPS) to modulate RA's effects. C57Bl/6 female mice were intranasally instilled once with 50 mul of RA (500 mug/kg body weight [bw]) in saline or saline only and then nose and brain tissues were collected over 72 h and processed for histopathologic and messenger RNA (mRNA) analysis. RA-induced apoptosis specifically in olfactory sensory neurons (OSNs) after 24 h postinstillation (PI) causing marked atrophy of olfactory epithelium (OE) that was maximal at 72 h PI. Concurrently, there was marked bilateral atrophy of olfactory nerve layer of the olfactory bulbs (OBs) of the brain. In the ethmoid turbinates, upregulated messenger RNA (mRNA) expression of the proapoptotic gene FAS and the proinflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-6, IL-1, and macrophage inhibitory protein-2 was observed from 6 to 24 h PI, whereas expression of several other proapoptotic genes (PKR, p53, Bax, and caspase-activated DNAse) was detectable only at 24 h PI. Simultaneous exposure to LPS (500 ng/kg bw) and a lower dose of RA (250 mug/kg bw) magnified RA-induced proinflammatory gene expression, apoptosis, and inflammation in the nasal tract. Taken together, the results suggest that RA markedly induced FAS and proinflammatory cytokine expression prior to evoking OSN apoptosis and OE atrophy and that RA's effects were augmented by LPS.
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PMID:Neurotoxicity and inflammation in the nasal airways of mice exposed to the macrocyclic trichothecene mycotoxin roridin a: kinetics and potentiation by bacterial lipopolysaccharide coexposure. 1748 19

beta-Hydroxy-beta-methylbutyrate (HMB; 50 microM) has been shown to attenuate the depression in protein synthesis in murine myotubes in response to lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha) with or without interferon-gamma (IFN-gamma), and angiotensin II (ANG II). The mechanism for the depression of protein synthesis by all three agents was the same and was attributed to activation of double-stranded RNA-dependent protein kinase (PKR) with the subsequent phosphorylation of eukaryotic initiation factor 2 (eIF2) on the alpha-subunit as well as increased phosphorylation of the elongation factor (eEF2). Myotubes expressing a catalytically inactive PKR variant, PKRDelta6, showed no depression of protein synthesis in response to either LPS or TNF-alpha, confirming the importance of PKR in this process. There was no effect of any of the agents on phosphorylation of mammalian target of rapamycin (mTOR) or initiation factor 4E-binding protein (4E-BP1), and thus no change in the amount of eIF4E bound to 4E-BP1 or the concentration of the active eIF4E.eIF4G complex. HMB attenuated phosphorylation of eEF2, possibly by increasing phosphorylation of mTOR, and also attenuated phosphorylation of eIF2alpha by preventing activation of PKR. These results suggest that HMB may be effective in attenuating muscle atrophy in a range of catabolic conditions.
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PMID:Attenuation of depression of muscle protein synthesis induced by lipopolysaccharide, tumor necrosis factor, and angiotensin II by beta-hydroxy-beta-methylbutyrate. 1885 27

Autotaxin (ATX) is a secreted enzyme with lysophospholipase D (lysoPLD) activity, which converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive phospholipid involved in numerous biological activities, including cell proliferation, differentiation, and migration. In the present study, we found that bacterial lipopolysaccharide (LPS), a well-known initiator of the inflammatory response, induced ATX expression in monocytic THP-1 cells. The activation of PKR, JNK, and p38 MAPK was required for the ATX induction. The LPS-induced ATX in THP-1 cells was characterized as the beta isoform. In the presence of LPC, ATX could promote the migrations of THP-1 and Jurkat cells, which was inhibited by pertussis toxin (PTX), an inhibitor of Gi-mediated LPA receptor signaling. In summary, LPS induces ATX expression in THP-1 cells via a PKR, JNK and p38 MAPK-mediated mechanism, and the ATX induction is likely to enhance immune cell migration in proinflammatory response by regulating LPA levels in the microenvironment.
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PMID:Lipopolysaccharide induces autotaxin expression in human monocytic THP-1 cells. 1902 16

The mechanism of the effect of beta-hydroxy-beta-methylbutyrate (HMB) on protein degradation induced by lipopolysaccharide (LPS) has been evaluated in murine myotubes. HMB (50 muM) completely attenuated total protein degradation induced by LPS (1-100 ng/ml), formation of reactive oxygen species (ROS) and activation of caspase-3/-8. Specific inhibitors of caspase-3/-8 completely attenuated ROS production, total protein degradation and the LPS-induced autophosphorylation of dsRNA-dependent protein kinase (PKR). Protein degradation in response to LPS or ROS production was not seen in myotubes transfected with mutant PKRDelta6, suggesting that PKR was involved in ROS production, which was essential for total protein degradation. This was confirmed using the antioxidant butylated hydroxytoluene (BHT) which completely attenuated protein degradation in response to LPS. The link between PKR activation and ROS production was mediated through p38 mitogen-activated protein kinase (MAPK), which was activated by LPS in myotubes transfected with wild-type PKR, but not PKRDelta6. Both ROS production and protein degradation induced by LPS were completely attenuated by SB203580, a specific inhibitor of p38MAPK. This suggests that LPS induces protein degradation through a signalling cascade involving activation of caspase-3/-8, activation of PKR and production of ROS through p38MAPK, and that this process is attenuated by HMB.
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PMID:Mechanism of attenuation by beta-hydroxy-beta-methylbutyrate of muscle protein degradation induced by lipopolysaccharide. 1940 20


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