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)

The production of nitric oxide by macrophages has been implicated as a host defense mechanism against microbial pathogens and tumor cells. Recent reports have implicated interferon-alpha/beta (IFN-alpha/beta) as an autocrine/paracrine signal critical for the induction of murine iNOS. In this report we have systematically investigated the role of IFN-beta in the induction of iNOS in the murine macrophage cell line, RAW 264.7. First, we demonstrate that IFN-beta expression is highly up-regulated, and is secreted in response to lipopolysaccharide (LPS). Treatment of RAW macrophages with LPS results in a time-dependent phosphorylation of STAT-1 on both tyrosine residue 701 (Tyr-701) and serine residue 727 (Ser-727) that is consistent with the timing of endogenous IFN-beta expression. LPS also induces interferon regulatory factor-1 expression with similar kinetics. We further demonstrate that exogenous IFN-beta accelerates the induction of iNOS by LPS. The acceleration of iNOS induction is observed at the levels of transcription, protein expression, and NO formation. Accordingly, we propose that the cytokine environment of macrophages may determine the rate and magnitude of nitric oxide production, thereby regulating the cytotoxic response to pathogen challenge.
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PMID:Lipopolysaccharide-induced expression of interferon-beta mediates the timing of inducible nitric-oxide synthase induction in RAW 264.7 macrophages. 1160 90

It was observed that interferon beta (IFN-beta) prevents the down-regulation of the interleukin-3 receptor alpha chain (IL-3Ralpha), which spontaneously occurs during culture of human monocytes. The functionality of IL-3R was demonstrated by the fact that IL-3 rescued IFN-beta-treated monocytes from apoptosis. Monocytes cultured in the presence of IFN-beta and IL-3 acquire a dendritic morphology and express high levels of HLA antigen class I and class II and costimulatory molecules. When stimulated by either lipopolysaccharide or fibroblasts expressing CD40 ligand (CD40L) transfectants, dendritic cells (DCs) generated in IFN-beta and IL-3 secreted high levels of IL-6, IL-8, and tumor necrosis factor-alpha but low levels of IL-12 in comparison with DCs generated in IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF). In mixed leukocyte culture, IL-3-IFN-beta DCs induced a vigorous proliferative response of allogeneic cord blood T cells and elicited the production of high levels of IFN-gamma and IL-5 by naive adult CD4+ T cells. Finally, IL-3-IFN-beta DCs were found to produce much higher levels of IFN-alpha than IL-4-GM-CSF DCs in response to Poly (I:C) but not to influenza virus. It was concluded that monocytes cultured in the presence of IL-3 and IFN-beta differentiate into DCs with potent helper T-cell stimulatory capacity despite their low secretion of IL-12.
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PMID:Interleukin-3 and interferon beta cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties. 1180 4

Toll-like receptor 2 (TLR2) agonists induce a subset of TLR4-inducible proinflammatory genes, which suggests the use of differential signaling pathways. Murine macrophages stimulated with the TLR4 agonist Escherichia coli lipopolysaccharide (LPS), but not with TLR2 agonists, induced phosphorylation of signal transducer and activator of transcription 1alpha (STAT1alpha) and STAT1beta, which was blocked by antibodies to interferon beta (IFN-beta) but not IFN-alpha. All TLR2 agonists poorly induced IFN-beta, which is encoded by an immediate early LPS-inducible gene. Thus, the failure of TLR2 agonists to induce STAT1-dependent genes resulted, in part, from their inability to express IFN-beta. TLR4-induced IFN-beta mRNA was MyD88- and PKR (double-stranded RNA-dependent protein kinase)-independent, but TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein)-dependent. Together, these findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists.
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PMID:TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. 1189 92

Toll-like receptor (TLR) can activate dendritic cells (DC) through common signaling pathways requiring a cytoplasmic adapter, MyD88. However, the signaling is differentially regulated among TLR family members. TLR4 can activate MyD88-deficient bone marrow-derived DC (BMDC), and lead to induction of IFN-inducible genes and up-regulation of co-stimulatory molecules such as CD40, implying that the MyD88-independent signaling pathway functions downstream of TLR4. Because these effects can also be induced by type I IFN, we have analyzed whether type I IFN is involved in TLR4-induced responses. In response to lipopolysaccharide (LPS), IFN-beta gene expression was augmented in both wild-type and MyD88-deficient BMDC. Expression of all IFN-inducible genes except immune-responsive gene 1 (IRG1) was abolished and CD40 up-regulation was decreased in LPS-stimulated BMDC lacking either IFN-alpha/beta receptor (IFN-alpha/betaR) or signal transducer and activator of transcription 1 (STAT-1). Similar to the LPS response, TLR9 signaling can also induce expression of IFN-beta and IFN-inducible genes, and up-regulation of CD40. However, all these effects were MyD88 dependent. Thus, in TLR4 signaling, IFN-beta expression can be induced either by the MyD88-dependent or -independent pathway, whereas, in TLR9 signaling, it is dependent on MyD88. In CpG DNA-stimulated DC, expression of IFN-inducible genes except IRG1 was dependent on type I IFN signaling as in LPS-stimulated DC. However, in contrast to TLR4 signaling, TLR9 signaling requires type I IFN signaling for CD40 up-regulation. Taken together, this study demonstrates differential involvement of type I IFN in TLR4- and TLR9-induced effects on DC.
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PMID:Differential involvement of IFN-beta in Toll-like receptor-stimulated dendritic cell activation. 1235 87

ISG15 is one of the most strongly induced genes upon viral infection, type I interferon (IFN) stimulation, and lipopolysaccharide (LPS) stimulation. Here we report that mice lacking UBP43, a protease that removes ISG15 from ISGylated proteins, are hypersensitive to type I IFN. Most importantly, in UBP43-deficient cells, IFN-beta induces a prolonged Stat1 tyrosine phosphorylation, DNA binding, and IFN-mediated gene activation. Furthermore, restoration of ISG15 conjugation in protein ISGylation-defective K562 cells increases IFN-stimulated promoter activity. These findings identify UBP43 as a novel negative regulator of IFN signaling and suggest the involvement of protein ISGylation in the regulation of the JAK-STAT pathway.
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PMID:Protein ISGylation modulates the JAK-STAT signaling pathway. 1260 Sep 39

We previously reported that Toll-like receptor-2 (TLR2) agonists induce expression of a more limited repertoire of pro-inflammatory genes than TLR4 agonists. Murine macrophages stimulated with the TLR4 agonist, Escherichia coli lipopolysaccharide, induced signal transducer and activator of transcription 1 ('STAT1') tyrosine phosphorylation that was secondary to the autocrine/paracrine action of interferon (IFN)-beta, an immediate early gene. In contrast, TLR2 agonists failed to activate IFN-beta gene expression. TLR4-induced IFN-beta mRNA was found to be MyD88- and PKR (double-stranded RNA-dependent protein kinase)-independent, but TIRAP (Toll/interleukin-1 receptor domain-containing adapter protein)/Mal (MyD88-adapter-like)-dependent. In the present paper, we outline the recent controversy over the role of TIRAP/Mal in TLR2 and TLR4 signalling in the context of the current molecular tools used for such studies. Collectively, our findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists.
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PMID:Toll-like receptor 4 signalling: new perspectives on a complex signal-transduction problem. 1277 78

Type I interferons (IFN-alpha/beta) affect many aspects of immune responses. Many pathogen-associated molecules, including bacterial lipopolysaccharide (LPS) and virus-associated double-stranded RNA, induce IFN gene expression through activation of distinct Toll-like receptors (TLRs). Although much has been studied about the activation of the transcription factor IRF-3 and induction of IFN-beta gene by the LPS-mediated TLR4 signaling, definitive evidence is missing about the actual role of IRF-3 in LPS responses in vitro and in vivo. Using IRF-3 deficient mice, we show here that IRF-3 is indeed essential for the LPS-mediated IFN-beta gene induction. Loss of IRF-3 also affects the expression of profile of other cytokine/chemokine genes. We also provide evidence that the LPS/TLR4 signaling activates IRF-7 to induce IFN-beta, if IRF-7 is induced by IFNs prior to LPS simulation. Finally, the IRF-3-deficient mice show resistance to LPS-induced endotoxin shock. These results place IRF-3 as a molecule central to LPS/TLR4 signaling.
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PMID:Essential role of IRF-3 in lipopolysaccharide-induced interferon-beta gene expression and endotoxin shock. 1282 Nov 21

Nitric oxide (NO) has an important cytotoxic role in host defense processes against invading microorganisms and neoplastic cells. Here we demonstrate the effect of culture density on the expression of NO synthase and NO production by lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. At high cell densities, the LPS-induced expression of iNOS message, protein, and activity is markedly enhanced. We demonstrate the effects to be mediated by a diffusible macrophage product. Increasing cell density correlates with activation of IFN-dependent signaling pathways. We observe enhanced phosphorylation of STAT-1 on tyrosine 701 and serine 727, and an increase in STAT-1 DNA binding. Expression of the IFN-stimulated transcription factor IRF-1 is also enhanced. The data are consistent with the reported involvement of IFN-beta as an autocrine co-activator of iNOS expression. Considering the importance of NO as a cytotoxic mediator of host immunity, the data suggest that macrophage density is important in regulating the magnitude of NO production, and thus, the host response to infection.
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PMID:Cell density-enhanced expression of inducible nitric oxide synthase in murine macrophages mediated by interferon-beta. 1289 31

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF/nerve growth factor superfamily that, apart from inducing cell death in susceptible cells, displays immunoregulatory functions influencing, for instance, T cell proliferation. It can be found in two forms: membrane-bound and soluble protein. The regulation of these is still not fully understood. In this study, we have analyzed the regulation of TRAIL surface expression and secretion in human T cells, B cells, and monocytes in response to specific stimuli. T cells, B cells, and monocytes were cultured in the presence of phytohemagglutinin (PHA)+interleukin (IL-2), anti-CD40+IL-4, and lipopolysaccharide (LPS), respectively. In particular, not only PHA+IL-2 but also LPS were able to induce secretion of soluble TRAIL, but did not enhance the expression of surface-bound TRAIL. Simultaneously, we investigated the effect of the pleiotropic stimulus interferon (IFN)-beta, known to target all leukocyte subsets, on TRAIL. Predominantly, monocytes were affected by IFN-beta, causing both release of soluble TRAIL and upregulation of the surface-bound form. IFN-beta, however, did not cause any upregulation of TRAIL in T cells. Our data serve as a basis to better understand the complex regulation of TRAIL in human peripheral immune cells and might help to clarify the role of the TRAIL system in immunopathology.
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PMID:Regulation of soluble and surface-bound TRAIL in human T cells, B cells, and monocytes. 1460 66

How lipopolysaccharide (LPS) signals through toll-like receptors (TLRs) to induce nuclear factor (NF)-kappa B inflammatory cytokines in sepsis remains unclear. Major candidates for that process are myeloid differentiation protein 88 (MyD88) and MyD88 adaptor-like/TIR domain-containing adaptor protein (Mal/TIRAP) but their role needs to be further defined. Here, we have examined the role of MyD88 and Mal/TIRAP in primary human cells of nonmyeloid and myeloid origin as physiologically relevant systems. We found that MyD88 and Mal/TIRAP are essential for LPS-induced I kappa B alpha phosphorylation, NF-kappa B activation, and interleukin 6 (IL-6) or IL-8 production in fibroblasts and endothelial cells in a pathway that also requires IKK2. In contrast, in macrophages neither MyD88, Mal/TIRAP, nor I kappa B kinase 2 (IKK2) are required for NF-kappa B activation or tumor necrosis factor alpha (TNF alpha), IL-6, or IL-8 production, although Mal/TIRAP is still involved in the production of interferon beta (IFN beta). Differential usage of TLRs may account for that, as in macrophages but not fibroblasts or endothelial cells, TLR4 is expressed in high levels at the cell surface, and neutralization of TLR4 but not TLR2 blocks LPS signaling. These observations demonstrate for the first time the existence of 2 distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of TLR4, MyD88, Mal/TIRAP, and IKK2, and reveal a layer of complexity not previously expected.
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PMID:Distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP. 1463 Aug 16


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