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 molecular mechanism by which the deleterious cytokines interleukin 1 beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) are induced in endotoxin-stimulated microglia was investigated from the viewpoint of signal transduction. Neither cytokine is produced in nonstimulated rat microglia, but both are remarkably induced by stimulation with endotoxin lipopolysaccharide (LPS). LPS-inducible IL-1beta was significantly suppressed by pretreatment with the nuclear factor kappa B (NFkappaB) inhibitor ammonium pyrrolidine dithiocarbamate (APDC), but TNFalpha was not. APDC was actually confirmed to suppress the degradation of IkappaBalpha and IkappaBbeta in microglia, indicating a role for the inhibitor of NFkappaB activation. Taken together, these results suggest that the induction of IL-1beta and TNFalpha in endotoxin-stimulated microglia is differentially regulated at the level of NFkappaB activation.
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PMID:Differential suppression of endotoxin-inducible inflammatory cytokines by nuclear factor kappa B (NFkappaB) inhibitor in rat microglia. 1658 Jan 31

Adjuvant-induced survival of T cells after antigen activation correlates with increased expression of Bcl-3. Bcl-3 is an NF-kappaB/IkappaB family member and has been implicated in transcriptional regulation in several cell types. We tested the ability of mice deficient in Bcl-3 (Bcl-3 KO) to exhibit T-cell adjuvant-induced survival after challenge with the superantigen staphylococcal enterotoxin B (SEB), using lipopolysaccharide (LPS) as a natural adjuvant. These studies showed that Bcl-3 is required for secondary gamma interferon (IFN-gamma) production by CD8 T cells but not for adjuvant-induced survival effects. Specifically, wild-type and Bcl-3 KO mice exhibited comparable long-term increases in the Vbeta8(+) T-cell populations, indicating no lack of survival in response to adjuvant stimulation in the Bcl-3 KO activated T cells. Ectopic expression of the Bcl-3-related molecules IkappaBalpha, IkappaBbeta, and IkappaBepsilon in SEB-activated T cells increased survival during in vitro culture in the absence of adjuvant, suggesting that these IkappaB molecules could exert a survival function in antigen-activated T cells in place of Bcl-3. However, Vbeta8(+) CD8 T cells from SEB- plus LPS-treated Bcl-3 KO mice produced less IFN-gamma upon in vitro restimulation than Vbeta8(+) CD8 T cells from wild-type mice. Therefore, Bcl-3 plays a unique role in the regulation of IFN-gamma production in this model system.
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PMID:CD8 T cells require Bcl-3 for maximal gamma interferon production upon secondary exposure to antigen. 1679 Jul 93

The serine anti-protease elafin is expressed by monocytes, alveolar macrophages, neutrophils, and at mucosal surfaces and possesses antimicrobial activity. It is also known to reduce lipopolysaccharide-induced neutrophil influx into murine alveoli as well as to abrogate lipopolysaccharide-induced production of matrix metalloprotease 9, macrophage inhibitory protein 2, and tumor necrosis factor-alpha by as-yet unidentified mechanisms. In this report we have shown that elafin inhibits the lipopolysaccharide-induced production of monocyte chemoattractant protein-1 in monocytes by inhibiting AP-1 and NF-kappaB activation. Elafin prevented lipopolysaccharide-induced phosphorylation of AP-1, c-Jun, and JNK but had no effect on phosphorylation of p38. The lipopolysaccharide-induced degradation of IL-1R-associated kinase 1, IkappaBalpha, and IkappaBbeta was inhibited by elafin but phosphorylation of IkappaBalpha was unaffected. Polyubiquitinated protein including polyubiquitinated IkappaBalpha was shown to accumulate in the presence of elafin. These results suggest that inhibition by elafin of lipopolysaccharide-induced AP-1 and NF-kappaB activation occurs via an effect on the ubiquitin-proteasome pathway.
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PMID:Elafin prevents lipopolysaccharide-induced AP-1 and NF-kappaB activation via an effect on the ubiquitin-proteasome pathway. 1698 Mar 10

The ability of neonatal and adult cardiomyocytes to activate the nuclear factor (NF)-kappaB pathway in response to lipopolysaccharide and interleukin-1beta challenge has been investigated and compared with that of peritoneal macrophages. The activation of the IkappaB kinase and the phosphorylation and degradation of IkappaBalpha and IkappaBbeta was much lower in adult cardiomyocytes than in the neonatal counterparts and macrophages. This restricted activation of the NF-kappaB pathway resulted in a significant reduction in the time of nuclear activation of NF-kappaB, as deduced by electrophoretic mobility shift assays and in the transcription of target genes, such as IkappaBalpha, cyclooxygenase-2 (COX-2) and nitric-oxide synthase-2 (NOS-2). Studies on chromatin immunoprecipitation showed binding of NF-kappaB proteins to the regulatory kappaB sites identified in the promoters of the IkappaBalpha, COX-2, and NOS-2 genes in macrophages and, to a lower extent, in neonatal cardiomyocytes. The binding to these kappaB sites in adult cardiomyocytes was observed only in the IkappaBalpha promoter and was minimal or absent in the COX-2 and NOS-2 promoters, respectively, suggesting a restricted activation of NF-kappaB-regulated genes in these cells. These data indicate that the function of the NF-kappaB pathway in adult cardiomyocytes is limited in time, which results in the expression of a reduced number of genes and provides a functional explanation for the absence of NOS-2 inducibility in these cells under proinflammatory conditions.
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PMID:Selective impairment of nuclear factor-kappaB-dependent gene transcription in adult cardiomyocytes: relevance for the regulation of the inflammatory response in the heart. 1767 83

Glyceryl nonivamide (GLNVA), a vanilloid receptor (VR) agonist, has been reported to have calcitonin gene-related peptide-associated vasodilatation and to prevent subarachnoid hemorrhage-induced cerebral vasospasm. In this study, we investigated the neuroprotective effects of GLNVA on activated microglia-like cell mediated- and proparkinsonian neurotoxin 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells. In coculture conditions, we used lipopolysaccharide (LPS)-stimulated BV-2 cells as a model of activated microglia. LPS-induced neuronal death was significantly inhibited by diphenylene iodonium (DPI), an inhibitor of NADPH oxidase. However, capsazepine, the selective VR1 antagonist, did not block the neuroprotective effects of GLNVA. GLNVA reduced LPS-activated microglia-mediated neuronal death, but it lacked protection in DPI-pretreated cultures. GLNVA also decreased LPS activated microglia induced overexpression of neuronal nitric-oxide synthase (nNOS) and glycoprotein 91 phagocyte oxidase (gp91(phox)) on SH-SY5Y cells. Pretreatment of BV-2 cells with GLNVA diminished LPS-induced nitric oxide production, overexpression of inducible nitric-oxide synthase (iNOS), and gp91(phox) and intracellular reactive oxygen species (iROS). GLNVA also reduced cyclooxygenase (COX)-2 expression, inhibitor of nuclear factor (NF)-kappaB (IkappaB)alpha/IkappaBbeta degradation, NF-kappaB activation, and the overproduction of tumor necrosis factor-alpha, interleukin (IL)-1beta, and prostaglandin E2 in BV-2 cells. However, GLNVA augmented anti-inflammatory cytokine IL-10 production on LPS-stimulated BV-2 cells. Furthermore, in 6-OHDA-treated SH-SY5Y cells, GLNVA rescued the changes in condensed nuclear and apoptotic bodies, prevented the decrease in mitochondrial membrane potential, and reduced cells death. GLNVA also suppressed accumulation of iROS and up-regulated heme oxygenase-1 expression. 6-OHDA-induced overexpression of nNOS, iNOS, COX-2, and gp91(phox) was also reduced by GLNVA. In summary, the neuroprotective effects of GLNVA are mediated, at least in part, by decreasing the inflammation- and oxidative stress-associated factors induced by microglia and 6-OHDA.
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PMID:Neuroprotective effects of glyceryl nonivamide against microglia-like cells and 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y human dopaminergic neuroblastoma cells. 1785 75

The activation of pro-inflammatory gene programs by nuclear factor-kappaB (NF-kappaB) is primarily regulated through cytoplasmic sequestration of NF-kappaB by the inhibitor of kappaB (IkappaB) family of proteins. IkappaBbeta, a major isoform of IkappaB, can sequester NF-kappaB in the cytoplasm, although its biological role remains unclear. Although cells lacking IkappaBbeta have been reported, in vivo studies have been limited and suggested redundancy between IkappaBalpha and IkappaBbeta. Like IkappaBalpha, IkappaBbeta is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus. The crystal structure of IkappaBbeta bound to p65 suggested this complex might bind DNA. In vitro, hypophosphorylated IkappaBbeta can bind DNA with p65 and c-Rel, and the DNA-bound NF-kappaB:IkappaBbeta complexes are resistant to IkappaBalpha, suggesting hypophosphorylated, nuclear IkappaBbeta may prolong the expression of certain genes. Here we report that in vivo IkappaBbeta serves both to inhibit and facilitate the inflammatory response. IkappaBbeta degradation releases NF-kappaB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-alpha (TNF-alpha). Surprisingly, absence of IkappaBbeta results in a dramatic reduction of TNF-alpha in response to LPS even though activation of NF-kappaB is normal. The inhibition of TNF-alpha messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IkappaBbeta bound to p65:c-Rel heterodimers at a specific kappaB site on the TNF-alpha promoter. Therefore IkappaBbeta acts through p65:c-Rel dimers to maintain prolonged expression of TNF-alpha. As a result, IkappaBbeta(-/-) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IkappaBbeta might be a promising new strategy for selectively inhibiting the chronic phase of TNF-alpha production during the inflammatory response.
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PMID:IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response. 2074 13


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