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)

Myeloid differentiation factor 88 (MyD88) plays essential roles in the signaling of the Toll/interleukin (IL)-1 receptor family. Toll-IL-1 receptor domain-containing adaptor inducing interferon-beta (TRIF)-mediated signals are involved in lipopolysaccharide (LPS)-induced MyD88-independent pathways. Using MyD88-deficient (MyD88-/-) mice and TRIF-deficient (TRIF-/-) mice, we examined roles of MyD88 and TRIF in osteoclast differentiation and function. LPS, diacyl lipopeptide, and IL-1alpha stimulated osteoclastogenesis in cocultures of osteoblasts and hemopoietic cells obtained from TRIF-/- mice, but not MyD88-/- mice. These factors stimulated receptor activator of nuclear factor-kappaB ligand mRNA expression in TRIF-/- osteoblasts, but not MyD88-/- osteoblasts. LPS stimulated IL-6 production in TRIF-/- osteoblasts, but not TRIF-/- macrophages. LPS and IL-1alpha enhanced the survival of TRIF-/- osteoclasts, but not MyD88-/- osteoclasts. Diacyl lipopeptide did not support the survival of osteoclasts because of the lack of Toll-like receptor (TLR)6 in osteoclasts. Macrophages expressed both TRIF and TRIF-related adaptor molecule (TRAM) mRNA, whereas osteoblasts and osteoclasts expressed only TRIF mRNA. Bone histomorphometry showed that MyD88-/- mice exhibited osteopenia with reduced bone resorption and formation. These results suggest that the MyD88-mediated signal is essential for the osteoclastogenesis and function induced by IL-1 and TLR ligands, and that MyD88 is physiologically involved in bone turnover.
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PMID:MyD88 but not TRIF is essential for osteoclastogenesis induced by lipopolysaccharide, diacyl lipopeptide, and IL-1alpha. 1535 53

An understanding of lipopolysaccharide (LPS) signal transduction is a key goal in the effort to provide a molecular basis for the lethal effect of LPS during septic shock and point the way to novel therapies. Rapid progress in this field during the last 6 years has resulted in the discovery of not only the receptor for LPS - Toll-like receptor 4 (TLR4) - but also in a better appreciation of the complexity of the signalling pathways activated by LPS. Soon after the discovery of TLR4, the formation of a receptor complex in response to LPS, consisting of dimerized TLR4 and MD-2, was described. Intracellular events following the formation of this receptor complex depend on different sets of adapters. An early response, which is dependent on MyD88 and MyD88-like adapter (Mal), leads to the activation of nuclear factor-kappaB (NF-kappaB). A later response to LPS makes use of TIR-domain-containing adapter-inducing interferon-beta (TRIF) and TRIF-related adapter molecule (TRAM), and leads to the late activation of NF-kappaB and IRF3, and to the induction of cytokines, chemokines, and other transcription factors. As LPS signal transduction is an area of intense research and rapid progress, this review is intended to sum up our present understanding of the events following LPS binding to TLR4, and we also attempt to create a model of the signalling pathways activated by LPS.
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PMID:Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. 1537 75

Influenza A is a highly contagious single-stranded RNA virus that infects both the upper and lower respiratory tracts of humans. The host innate immune Toll-like receptor (TLR) 3 was shown previously in cells of myeloid origin to recognize the viral replicative, intermediate double-stranded RNA (dsRNA). Thus, dsRNA may be critical for the outcome of the infection. Here we first compared the activation triggered by either influenza A virus or dsRNA in pulmonary epithelial cells. We established that TLR3 is constitutively expressed in human alveolar and bronchial epithelial cells, and we describe its intracellular localization. Expression of TLR3 was positively regulated by the influenza A virus and by dsRNA but not by other inflammatory mediators, including bacterial lipopolysaccharide, the cytokines tumor necrosis factor-alpha and interleukin (IL)-1beta, and the protein kinase C activator phorbol 12-myristate 13-acetate. We also demonstrated that TLR3 contributes directly to the immune response of respiratory epithelial cells to influenza A virus and dsRNA, and we propose a molecular mechanism by which these stimuli induce epithelial cell activation. This model involves mitogen-activated protein kinases, phosphatidylinositol 3-kinase/Akt signaling, and the TLR3-associated adaptor molecule TRIF but not MyD88-dependent activation of the transcription factors NF-kappaB or interferon regulatory factor/interferon-sensitive response-element pathways. Ultimately, this signal transduction elicits an epithelial response that includes the secretion of the cytokines IL-8, IL-6, RANTES (regulated on activation normal T cell expressed and secreted), and interferon-beta and the up-regulation of the major adhesion molecule ICAM-1.
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PMID:Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. 1557

1'S-1'-Acetoxychavicol acetate from the rhizomes of Alpinia galanga was known to show potent inhibitory effect on the production of nitric oxide (NO) in lipopolysaccharide-activated mouse peritoneal macrophages. To clarify its mechanism of action, the effects of 1'S-1'-acetoxychavicol acetate on the expression of interferon-beta (IFN-beta) mRNA and activation of nuclear factor-kappaB (NF-kappaB), both of which participate in the induction of inducible NO synthase, were examined in lipopolysaccharide-activated macrophages. The results were compared with those of two inhibitors of the NF-kappaB activation, costunolide and caffeic acid phenethyl ester. 1'S-1'-Acetoxychavicol acetate inhibited IFN-beta mRNA expression as well as NF-kappaB activation, and two related compounds, (+/-)-1-acetoxy-1-(2-acetoxyphenyl)-2-propene and (+/-)-1-acetoxy-1-(4-acetoxyphenol)-3-butene, also inhibited IFN-beta mRNA expression. In addition, 1'S-1'-acetoxychavicol acetate inhibited the production of NO stimulated by poly(I:C) via Toll-like receptor 3.
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PMID:1'S-1'-Acetoxychavicol acetate as a new type inhibitor of interferon-beta production in lipopolysaccharide-activated mouse peritoneal macrophages. 1580 64

Nitric oxide (NO) produced by macrophages plays an important role in host defense and inflammation. We found that two agrochemicals, alachlor and carbaryl, inhibit lipopolysaccharide (LPS)-induced NO production by macrophages. In the present study, we investigated this inhibitory mechanism in RAW 264 cells. Both chemicals inhibited LPS-induced iNOS protein and mRNA expression as well as murine iNOS promoter activity. When treating these chemicals with reducing agents, the inhibition by carbaryl was reversed, but not the inhibition by alachlor. These chemicals also inhibited LPS-induced interferon-beta (IFN-beta) expression, an indispensable factor for LPS-induced iNOS expression. The inhibited iNOS expression, however, was not restored by exogenous IFN-beta supplementation. LPS-induced nuclear translocation of NF-kappaB, which is necessary for the expression of IFN-beta and iNOS, was inhibited by these chemicals: however, the LPS-induced degradation of IkappaB-alpha and IkappaB-beta was inhibited only by alachlor. These results indicate that alachlor and carbaryl differentially impair the LPS-induced NF-kappaB activation, leading to the inhibition of NO production.
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PMID:Alachlor and carbaryl suppress lipopolysaccharide-induced iNOS expression by differentially inhibiting NF-kappaB activation. 1590 90

CD40 is expressed on various immune cells, including macrophages and microglia. Aberrant expression of CD40 is associated with autoimmune inflammatory diseases such as multiple sclerosis and rheumatoid arthritis. Interaction of Toll-like receptor-4 (TLR4) with the Gram-negative bacteria endotoxin lipopolysaccharide (LPS) results in the induction of an array of immune response genes. In this study, we describe that LPS is a strong inducer of CD40 expression in macrophages and microglia, which occurs at the transcriptional level and involves the activation of the transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 1alpha (STAT-1alpha). LPS-induced CD40 expression involves the endogenous production of the cytokine interferon-beta (IFN-beta), which contributes to CD40 expression by the activation of STAT-1alpha. Blocking IFN-beta-induced activation of STAT-1alpha by IFN-beta-neutralizing antibody reduces LPS-induced CD40 gene expression. Furthermore, LPS induces acetylation and phosphorylation of histones H3 and H4 and the recruitment of NF-kappaB, STAT-1alpha, and RNA polymerase II on the CD40 promoter in vivo in a time-dependent manner, all events important for CD40 gene transcription. These results indicate that both LPS-induced NF-kappaB activation and endogenous production of IFN-beta that subsequently induces STAT-1alpha activation play critical roles in the transcriptional activation of the CD40 gene by LPS.
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PMID:LPS induces CD40 gene expression through the activation of NF-kappaB and STAT-1alpha in macrophages and microglia. 1602 May 13

Cholesterols are enriched in the brain and can be oxidized to oxysterols by several processes. Oxysterols are transport forms of cholesterols across cell membranes and the blood-brain barrier. Here, to elucidate the roles of oxysterols in brain inflammation, we treated lipopolysaccharide-stimulated rat brain astrocytes with two oxysterols, 7-ketocholesterol and 22(R)-hydroxycholesterol. Both oxysterols suppressed inducible nitric oxide synthase expression and nitric oxide release as well as upstream signaling molecules including interferon-beta, phosphorylated signal transducer and activator of transcription 1/3, and interferon regulatory factor-1. Oxysterols are known as liver X receptor agonists, and inhibitory effects were also observed with synthetic agonists of liver X receptor and retinoid X receptor. Thus, we conclude that it is most likely mediated by liver X receptor/retinoid X receptor heterodimers.
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PMID:Oxysterols suppress inducible nitric oxide synthase expression in lipopolysaccharide-stimulated astrocytes through liver X receptor. 1640 68

Uptake of modified lipoproteins by macrophages results in the formation of foam cells. We investigated how foam cell formation affects the inflammatory response of macrophages. Murine bone marrow-derived macrophages were treated with oxidized LDL (oxLDL) to induce foam cell formation. Subsequently, the foam cells were activated with lipopolysaccharide (LPS), and the expression of lipid metabolism and inflammatory genes was analyzed. Furthermore, gene expression profiles of foam cells were analyzed using a microarray. We found that prior exposure to oxLDL resulted in enhanced LPS-induced tumor necrosis factor (TNF) and interleukin-6 (IL-6) gene expression, whereas the expression of the anti-inflammatory cytokine IL-10 and interferon-beta was decreased in foam cells. Also, LPS-induced cytokine secretion of TNF, IL-6, and IL-12 was enhanced, whereas secretion of IL-10 was strongly reduced after oxLDL preincubation. Microarray experiments showed that the overall inflammatory response induced by LPS was enhanced by oxLDL loading of the macrophages. Moreover, oxLDL loading was shown to result in increased nuclear factor-kappaB activation. In conclusion, our experiments show that the inflammatory response to LPS is enhanced by loading of macrophages with oxLDL. These data demonstrate that foam cell formation may augment the inflammatory response of macrophages during atherogenesis, possibly in an IL-10-dependent manner.
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PMID:Lipopolysaccharide-induced gene expression in murine macrophages is enhanced by prior exposure to oxLDL. 1684 Jul 96

Interferon-beta (IFN-beta) has been identified as the signature cytokine induced via the Toll-like receptor (TLR) 4, "MyD88-independent" signaling pathway in macrophages stimulated by Gram-negative bacterial lipopolysaccharide (LPS). In this study, we analyzed the responses of macrophages derived from wild-type (IFN-beta(+/+)) mice or mice with a targeted mutation in IFN-beta (IFN-beta(-/-)) to the prototype TLR4 agonist, Escherichia coli LPS. A comparison of basal and LPS-induced gene expression (by reverse transcription-PCR, real-time PCR, and Affymetrix microarray analyses) resulted in the identification of four distinct patterns of gene expression affected by IFN-beta deficiency. Analysis of a subset of each group of differentially regulated genes by computer-assisted promoter analysis revealed putative IFN-responsive elements in all genes examined. LPS-induced activation of intracellular signaling molecules, STAT1 Tyr-701, STAT1 Ser-727, and Akt, but not p38, JNK, and ERK MAPK proteins, was significantly diminished in IFN-beta(-/-) versus IFN-beta(+/+) macrophages. "Priming" of IFN-beta(-/-) macrophages with exogenous recombinant IFN-beta significantly increased levels of LPS-induced gene expression for induction of monocyte chemotactic protein 5, inducible nitric-oxide synthase, IP-10, and IL-12 p40 mRNA, whereas no increase or relatively small increases were observed for IL-1beta, IL-6, monocyte chemotactic protein 1, and MyD88 mRNA. Finally, IFN-beta(-/-) mice challenged in vivo with LPS exhibited increased survival when compared with wild-type IFN-beta(+/+) controls, indicating that IFN-beta contributes to LPS-induced lethality; however, not to the extent that one observes in mice with more complete pathway deficiencies (e.g. TLR4(-/-) or TRIF(-/-) mice). Collectively, these findings reveal unanticipated regulatory roles for IFN-beta in response to LPS in vitro and in vivo.
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PMID:Contribution of interferon-beta to the murine macrophage response to the toll-like receptor 4 agonist, lipopolysaccharide. 1691 41

Because the induction of interleukin-1beta (IL-1beta) is critical to antibacterial host defenses and its excessive generation is a prominent component of sepsis, regulation of this proinflammatory cytokine is a critical factor in the immune response to lipopolysaccharide (LPS). We previously showed that LPS-induced IL-1beta expression was regulated by a Stat1-dependent, nitric oxide (NO)-mediated mechanism. Subsequent in vivo studies showed that whereas Stat1 had a role in the downregulation of IL-1beta expression, it had a more significant effect on its initial induction. Although both interferon-beta (IFN-beta) and IFN-gamma activate Stat1, the early appearance of IFN-beta in the circulation after LPS administration suggested its pivotal role in Stat1-mediated IL-1beta expression in vivo. Further in vitro analysis of peritoneal macrophages from IFN-beta (/), Stat1(/), and caspase-1(/) mice and their wild-type controls following LPS stimulation demonstrated that IL-1beta mRNA was expressed in these mice but not in macrophages from MyD88(/) mice. Despite the presence of IL-1beta mRNA, IL-1beta protein was markedly reduced in the absence of Stat1 activation in macrophages derived from IFN-beta (/) and Stat1(/) mice or in the absence of caspase-1 activity, which itself was dependent on Stat1 activation. These studies support the hypothesis that the expression of IL-1beta requires both the MyD88-dependent induction of IL-1beta mRNA and pro-IL-1beta as well as the MyD88-independent, Stat1-mediated processing of that gene product into active cytokine.
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PMID:A role for Stat1 in the regulation of lipopolysaccharide-induced interleukin-1beta expression. 1703 68


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