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)

Exposure of macrophages to lipopolysaccharide (LPS) leads to production of the pro-inflammatory cytokine, tumour necrosis factor alpha (TNF-alpha). Previous studies have suggested that pathogenic Yersinia spp. inhibit LPS-mediated production of TNF-alpha in macrophages, and that one of the Yop proteins secreted by the plasmid-encoded type III pathway is required for this activity. We found that TNF-alpha production was inhibited when J774A.1 murine macrophages were infected with wild-type Y. pseudotuberculosis but not with an isogenic ysc mutant defective for Yop secretion. We inactivated multiple yop genes to identify which of these factors are required for the inhibition of TNF-alpha production. A mutant unable to express yopJ was defective for the inhibition of TNF-alpha production. Production of TNF-alpha is regulated at the transcriptional and translational levels by several mitogen-activated protein (MAP) kinases. The MAP kinases p38 and JNK underwent sustained activation in macrophages infected with the yopJ mutant. Conversely, p38 and JNK were downregulated in macrophages infected with the wild-type strain. The ability of the yopJ mutant to downregulate p38 and JNK and to inhibit production of TNF-alpha was restored by the expression of yopJ+ in trans. Therefore, YopJ is required for Y. pseudotuberculosis to downregulate MAP kinases and inhibit the production of TNF-alpha in macrophages.
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PMID:YopJ of Yersinia pseudotuberculosis is required for the inhibition of macrophage TNF-alpha production and downregulation of the MAP kinases p38 and JNK. 953 85

To test whether mitogen-activated protein kinases (MAPKs) are involved in microglial activation, pure microglia prepared from 1- to 3-day-old rat brains were activated with either 100 ng/ml lipopolysaccharide (LPS) or 5 nM synthetic beta-amyloid (Abeta) (25-35). The patterns of MAPK activation following LPS and Abeta treatment were very similar. Three MAPK subtypes, p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) were activated within 15 min and the activities of p38 and ERK were rapidly reduced to background level within 30 min while that of JNK was maintained for over 1 h. Both inhibitors of p38 (SB203580) and ERK pathway (PD098059) reduced LPS-induced nitric oxide (NO) release and Abeta-induced tumor necrosis factor-alpha (TNF-alpha) release. Furthermore, co-treatment of SB203580 and PD098059 additively reduced NO and TNF-alpha release. These results suggest that MAPK, at least p38 and ERK, mediate LPS-, and Abeta-induced microglial activation.
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PMID:Mitogen-activated protein kinases activated by lipopolysaccharide and beta-amyloid in cultured rat microglia. 957 82

Effects of antioxidants, resveratrol, quercetin, and N-acetylcysteine (NAC) on the functions of cultured rat hepatic stellate cells and Kupffer cells were studied. These compounds dose-dependently suppressed serum-dependent proliferation of stellate cells as determined by [3H]thymidine and 5-bromo-2'-deoxyuridine uptake. Expression of smooth muscle alpha-actin was suppressed by a high dose of resveratrol and quercetin. These phenolic compounds also suppressed inositol phosphate metabolism, tyrosine phosphorylation, and mitogen-activated protein (MAP) kinase activation in platelet-derived growth factor/BB-stimulated stellate cells. Moreover, the phenolic compounds selectively reduced the level of cell cycle protein cyclin D1 in stellate cells. Thus, resveratrol and quercetin might inhibit stellate cell activation by perturbing signal transduction pathway and cell cycle protein expression, whereas mechanism of potent antiproliferative effect of NAC remains to be elucidated. On the other hand, kinetic analysis showed that production of nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) by lipopolysaccharide-stimulated Kupffer cells was strongly inhibited by resveratrol and quercetin but not by NAC. Although expression of messenger RNAs for inducible NO synthase and TNF-alpha was not affected by the phenolic compounds, cellular levels of inducible NO synthase and TNF-alpha secretion were suppressed significantly, indicating the posttranscriptional process of generating these proteins might be affected predominantly by these phenolic compounds. Thus, NAC and these phenolic compounds may have therapeutic potential against liver injury by regulating functions of hepatic stellate cells and Kupffer cells.
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PMID:Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. 958 80

Accumulating evidence suggests that the insect and mammalian innate immune response is mediated by homologous regulatory components. Proinflammatory cytokines and bacterial lipopolysaccharide stimulate mammalian immunity by activating transcription factors such as NF-kappaB and AP-1. One of the responses evoked by these stimuli is the initiation of a kinase cascade that leads to the phosphorylation of p38 mitogen-activated protein (MAP) kinase on Thr and Tyr within the motif Thr-Gly-Tyr, which is located within subdomain VIII. We have investigated the possible involvement of the p38 MAP kinase pathway in the Drosophila immune response. Two genes that are highly homologous to the mammalian p38 MAP kinase were molecularly cloned and characterized. Furthermore, genes that encode two novel Drosophila MAP kinase kinases, D-MKK3 and D-MKK4, were identified. D-MKK3 is an efficient activator of both Drosophila p38 MAP kinases, while D-MKK4 is an activator of D-JNK but not D-p38. These data establish that Drosophila indeed possesses a conserved p38 MAP kinase signaling pathway. We have examined the role of the D-p38 MAP kinases in the regulation of insect immunity. The results revealed that one of the functions of D-p38 is to attenuate antimicrobial peptide gene expression following exposure to lipopolysaccharide.
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PMID:A conserved p38 mitogen-activated protein kinase pathway regulates Drosophila immunity gene expression. 958 93

Polycyclic aromatic hydrocarbons (PAH) contained in fossil fuel combustion particles enhance the allergic response to common environmental Ags. A key question is: what are molecular pathways in the immune system by which PAH and conversion products drive allergic inflammation? Circumstantial evidence suggests that macrophages are involved in PAH-induced responses. We demonstrate that a representative PAH, beta-napthoflavone (BNF), and a representative quinone metabolite, tert-butylhydroxyquinone (tBHQ), induce Jun kinase and p38 mitogen-activated protein kinase activities in parallel with the generation of activator protein-1 (AP-1) mobility shift complexes in THP-1 and RAW264.7 macrophage cell lines. Activation of mitogen-activated protein kinases was dependent on generation of oxidative stress, and could be inhibited by N-acetylcysteine. Another genetic response pathway linked to PAH is the antioxidant response element (ARE), which regulates expression of detoxifying enzymes. BNF and tBHQ activated a human ARE (hARE) reporter gene in RAW264.7 cells. Interestingly, bacterial lipopolysaccharide also induced hARE/chloramphenicol acetyltransferase activity. While the hARE core, GTGACTCAGC, contains a consensus AP-1 sequence (underlined), AP-1 was not required for hARE activation. This suggests that PAH and their conversion products operate via ARE-specific transcription factors in the immune system. BNF and tBHQ did, however, induce AP-1 binding to the hARE, while constitutively active Jun kinase interfered in hARE/chloramphenicol acetyltransferase activation. This suggests that AP-1 proteins negatively regulate the hARE. These data establish important activation pathways for PAH in the immune system and provide us with targets to modulate the effect of environmental pollutants on allergic inflammation.
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PMID:Macrophage activation by polycyclic aromatic hydrocarbons: evidence for the involvement of stress-activated protein kinases, activator protein-1, and antioxidant response elements. 967 Sep 73

Previous studies have suggested that the P2Z/P2X7 purinergic receptor can participate in nucleotide-induced modulation of lipopolysaccharide (LPS) stimulated inflammatory mediator production. To test this hypothesis, we evaluated whether antagonism of the P2Z/P2X7 receptor can influence LPS signaling and expression of the inducible form of nitric-oxide synthase (iNOS) in RAW 264.7 macrophages. In the present study, we demonstrate that pretreatment of RAW 264.7 macrophages with a P2Z/P2X7 receptor antagonist, periodate oxidized adenosine 5'-triphosphate (o-ATP), substantially inhibits LPS-stimulated NO production and iNOS expression without altering cell viability. This effect on LPS-induced iNOS expression is mimicked by a pyridoxal-phosphate-based antagonist (pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid) of the P2Z/P2X7 purinergic receptor, indicating that these results are not unique to o-ATP. Additionally, o-ATP prevents cell death induced by P2Z/P2X7 receptor agonists. To ascertain how P2Z/P2X7 receptor antagonists influence LPS signaling, we evaluated the capacity of o-ATP to regulate LPS-mediated activation of the transcription factor, nuclear factor-kappaB, and the mitogen-activated protein kinases, extracellular signal-regulated kinase (ERK) 1 and ERK2. These experiments reveal that pretreatment of RAW 264.7 cells with o-ATP attenuates the LPS stimulation of a nuclear factor-kappaB-like binding activity. Moreover, the activation of ERK1 and ERK2 by LPS, but not by the phorbol ester, phorbol 12-myristate 13-acetate, is also blocked in RAW 264.7 cells by o-ATP pretreatment. In summary, these data suggest that the P2Z/P2X7 receptor modulates LPS-induced macrophage activation as assessed by iNOS expression and NO production. This report implicates the P2Z/P2X7 receptor in the control of protein kinase cascades and transcriptional processes, and these observations are likely to be important for the development of selective purinergic receptor antagonists for the treatment of septic shock.
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PMID:Purinergic receptor modulation of lipopolysaccharide signaling and inducible nitric-oxide synthase expression in RAW 264.7 macrophages. 976 36

Nitric oxide production by macrophages is principally regulated by the calcium-independent enzyme, inducible nitric oxide synthase (iNOS). Both lipopolysaccharide and TNF-alpha synergize with IFN-gamma in the expression of iNOS with subsequent production of nitric oxide. Previous work has shown that IL-4 downregulates iNOS and nitric oxide expression by macrophages stimulated with LPS and IFN-gamma. In this study, we found that IL-4 also downregulated iNOS and nitric oxide expression induced by IFN-gamma and TNF-alpha and in mouse macrophages. Because various members of the mitogen-activated protein kinases and their upstream kinases have been shown to directly or indirectly activate a number of transcription factors including AP-1 and NFkappaB, we examined the effects of IL-4 on TNF-alpha activation of the MAPKs. Our results show that IL-4 modestly inhibited JNK/SAPK and ERK activation by TNF-alpha. Previously, we showed that selective pharmacologic inhibition of the ERK and/or p38mapk pathway did not affect NO2- expression. Treatment of cells with the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) showed a dose-response inhibition of NO2- expression. NPPB was also found to inhibit ERK and JNK/SAPK activation but not p38mapk with TNF-alpha stimulation. The discordance between the marked degree of inhibition of iNOS transcript by IL-4 and the modest inhibition of JNK/SAPK and ERK suggests that the mechanism by which IL-4 inhibits iNOS transcription appears more complex than a mere inhibition of these MAPKs.
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PMID:Potential role of the JNK/SAPK signal transduction pathway in the induction of iNOS by TNF-alpha. 991 6

Protein kinase C (PKC)-alpha, -betaI, and -delta are known to be involved in the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. The role of mitogen-activated protein kinases (MAPK) p44/42 and p38 in the LPS effect was studied further. LPS-mediated NO release and the inducible form of NO synthase expression were inhibited by the p38 inhibitor, SB 203580, but not by the MAPK kinase inhibitor, PD 98059. Ten-minute treatment of cells with LPS resulted in the activation of p44/42 MAPK, p38, and c-Jun NH2-terminal kinase. Marked or slight activation, respectively, of p44/42 MAPK or p38 was also seen after 10-min treatment with 12-O-tetradecanoylphorbol-13-acetate, but c-Jun NH2-terminal kinase activation did not occur. Tyrosine kinase inhibitor, genestein, attenuated the LPS-induced activation of both p44/42 MAPK and p38, whereas the PKC inhibitors, Ro 31-8220 and calphostin C, or long-term treatment with 12-O-tetradecanoylphorbol-13-acetate resulted in inhibition of p44/42 MAPK activation, but had only a slight effect on p38 activation, indicating that LPS-mediated PKC activation resulted in the activation of p44/42 MAPK. Nuclear factor-kappaB (NF-kappaB)-specific DNA-protein-binding activity in the nuclear extracts was enhanced by 10-min, 1-h, or 24-h treatment with LPS. Analysis of the proteins involved in NF-kappaB binding showed translocation of p65 from the cytosol to the nucleus after 10-min treatment with LPS. The onset of NF-kappaB activation correlated with the cytosolic degradation of both inhibitory proteins of NF-kappaB, IkappaB-alpha and IkappaB-beta. IkappaB-alpha was resynthesized rapidly after loss (1-h LPS treatment), whereas IkappaB-beta levels were not restored until after 24-h treatment. SB 203580 but not PD 98059 inhibited the LPS-induced stimulation of NF-kappaB DNA-protein binding. Thus, activation of p38 but not p44/42 MAPK by LPS resulted in the stimulation of NF-kappaB-specific DNA-protein binding and the subsequent expression of inducible form of NO synthase and NO release in RAW 264.7 macrophages.
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PMID:p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. 1005 31

Nitric oxide (NO) produced by inducible nitric-oxide synthase (iNOS) in different cells including brain cells in response to proinflammatory cytokines plays an important role in the pathophysiology of demyelinating and neurodegenerative diseases. The present study underlines the importance of phosphatidylinositol 3-kinase (PI 3-kinase) in the expression of iNOS in C6 glial cells and rat primary astrocytes. Bacterial lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) was unable to induce the expression of iNOS and the production of NO in rat C6 glial cells. Similarly, wortmannin and LY294002, compounds that inhibit PI 3-kinase, were also unable to induce the expression of iNOS and the production of NO. However, a combination of wortmannin or LY294002 with LPS or IL-1beta induced the expression of iNOS and the production of NO in C6 glial cells. Consistent with the induction of iNOS, wortmannin also induced iNOS promoter-derived chloramphenicol acetyltransferase activity in LPS- or IL-1beta-treated C6 glial cells. The expression of iNOS by LPS in C6 glial cells expressing a dominant-negative mutant of p85alpha, the regulatory subunit of PI 3-kinase, further supports the conclusion that inhibition of PI 3-kinase provides a necessary signal for the induction of iNOS. Next we examined the effect of wortmannin on the activation of mitogen-activated protein (MAP) kinase and nuclear factor NF-kappaB in LPS- or IL-1beta-stimulated C6 glial cells. In contrast to the inability of LPS and IL-1beta alone to induce the expression of iNOS, both LPS and IL-1beta individually stimulated MAP kinase activity and induced DNA binding and transcriptional activity of NF-kappaB. Wortmannin alone was unable to activate MAP kinase and NF-kappaB. Moreover, wortmannin had no effect on LPS- or IL-1beta-mediated activation of MAP kinase and NF-kappaB, suggesting that wortmannin induced the expression of iNOS in LPS- or IL-1beta-stimulated C6 glial cells without modulating the activation of MAP kinase and NF-kappaB. Similar to C6 glial cells, wortmannin also stimulated LPS-mediated expression of iNOS and production of NO in astrocytes without affecting the LPS-mediated activation of NF-kappaB. Taken together, the results from specific chemical inhibitors and dominant-negative mutant expression studies demonstrate that apart from the activation of NF-kappaB, inhibition of PI 3-kinase is also necessary for the expression of iNOS and production of NO.
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PMID:Inhibition of phosphatidylinositol 3-kinase induces nitric-oxide synthase in lipopolysaccharide- or cytokine-stimulated C6 glial cells. 1006 20

The involvement of ceramide in lipopolysaccharide-mediated activation of mouse macrophages was studied. Lipopolysaccharide, cell-permeable ceramide analogs, and bacterial sphingomyelinase led to phosphorylation of the extracellular signal-regulated kinases, c-Jun NH2-terminal kinases, and p38 kinase and induced AP-1 DNA binding in C3H/OuJ (Lpsn) but not in C3H/HeJ (Lpsd) macrophages. Lipopolysaccharide and ceramide mimetics showed distinct kinetics of mitogen-activated protein kinase phosphorylation and AP-1 induction and activated AP-1 complexes with different subunit compositions. Lipopolysaccharide-activated AP-1 consisted of c-Fos, Jun-B, Jun-D, and c-Jun, while C2-ceramide induced Jun-D and c-Jun only. Lipopolysaccharide and, less potently, C2-ceramide or sphingomyelinase, stimulated AP-1-dependent reporter gene transcription in RAW 264.7 cells. Unlike lipopolysaccharide, C2-ceramide failed to activate NF-kappaB and did not induce production of tumor necrosis factor or interleukin-6. The lipopolysaccharide antagonist, Rhodobacter sphae-roides diphosphoryl lipid A, inhibited lipopolysaccharide activation of NF-kappaB and AP-1 but did not block C2-ceramide-induced AP-1. Pretreatment of C3H/OuJ macrophages with C2-ceramide greatly diminished AP-1 induction following subsequent C2-ceramide stimulation. However, lipopolysaccharide-induced transcription factor activation and cytokine release were not influenced. In contrast, lipopolysaccharide pretreatment inhibited both lipopolysaccharide- and C2-ceramide-mediated responses. Thus, ceramide partially mimics lipopolysaccharide in activating the mitogen-activated protein kinases and AP-1 but not in mediating NF-kappaB induction or cytokine production, suggesting a limited role in lipopolysaccharide signaling.
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PMID:Limited role of ceramide in lipopolysaccharide-mediated mitogen-activated protein kinase activation, transcription factor induction, and cytokine release. 1009 12


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