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)

Binding of many cytokines to their cognate receptors immediately activates Jak tyrosine kinases and their substrates, STAT (signal transducers and activators of transcription) DNA-binding proteins. The DNA binding targets of STATs are sequence elements related to the archetypal gamma interferon activation site, GAS. However, association of interleukin 1 (IL-1) with Jak-STAT signaling has remained unresolved. We now report an element termed LILRE (lipopolysaccharide [LPS] and IL-1-responsive element) in the human prointerleukin 1beta gene (IL1B) which can be immediately induced by either lipopolysaccharide (LPS) or IL-1 protein to bind a tyrosine-phosphorylated protein. This LPS- and IL-1-induced factor (LIL factor) is recognized by an antibody raised against the N terminus of Stat1, but not by those specific for either the C terminus of Stat1 or any other GAS-binding STAT. Phosphotyrosine (P-Tyr) specifically inhibits formation of the LIL factor-DNA complex, suggesting the importance of P-Tyr for the DNA-binding activity, as has been found for all STAT dimers. Analysis of DNA-binding specificity demonstrates that the LIL factor possesses a novel GAS-like binding activity that contrasts with those of other STATs in a requirement for a G residue at position 8 (TTCCTGAGA). Further investigation has revealed that IL-6, but neither IL-4 nor gamma interferon, activates the LIL factor. Thus, the existence of such a STAT-like factor (LIL-Stat) relates the LPS and IL-1 signaling pathway to other cytokine receptor signaling pathways via the activation of STATs. Moreover, the unique DNA-binding specificity and antigenicity of this factor suggest that LPS, IL-1, and IL-6 may use a common signaling pathway.
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PMID:A novel STAT-like factor mediates lipopolysaccharide, interleukin 1 (IL-1), and IL-6 signaling and recognizes a gamma interferon activation site-like element in the IL1B gene. 862 85

Induction of gene expression in cytokine-treated cells involves the protein tyrosine kinase-dependent activation of members of the STAT family of transcription factors. To determine if lipopolysaccharide (LPS) might activate one or more STAT factors, nuclear extracts from LPS-treated RAW264.7 macrophages were assayed for STAT-like DNA binding activity using oligonucleotides recognized by different members of this protein family. Within 30 min a single LPS-inducible DNA-protein complex was detected using three separate oligonucleotides. This activity was not reactive with anti-STAT antibodies and was subsequently identified as composed of the NF kappa B components NF kappa B1 and Rel-A. Thus, LPS does not directly stimulate STAT factors with known sequence-specific DNA binding activity.
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PMID:LPS does not directly induce STAT activity in mouse macrophages. 866 Jul 95

Control of cell proliferation involves a finely interwoven network of positive and negative cell cycle regulators. Signal transduction pathways linking c-fms (CSF-1R) to cellular proliferation and differentiation are being explored. Part of the strategy is to use a series of G1 inhibitors to help pinpoint relevant targets. Several inhibitors-8Br-cAMP, interferon gamma (IFN gamma), INF alpha/beta, lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF alpha), and dimethylamiloride-suppress CSF-1-stimulated proliferation in murine bone marrow-derived macrophages (BMM) even when added in the mid- to late-G1 phase of the cell cycle. The down-modulating effects of the inhibitors on the expression of the following cell cycle regulators have been examined: c-myc, cyclin D1 and D2, cdk4, Rb phosphorylation, E2F binding activity, ribonucleotide reductase subunits, and PCNA. Some differences in the negative control of such regulators were found, for example, in the manner in which IFN gamma and cAMP down-regulate c-myc expression. Using blocking antibodies and BMM from type I IFN receptor knockout mice, it appears that one of these inhibitors, IFN alpha/beta, acts as an endogenous inhibitor in CSF-1-treated BMM and is also responsible, at least in part, for the inhibition of cell cycle progression by LPS and TNF alpha. Another strategy has been to attempt to relate early biochemical changes induced by CSF-1 to later changes in the G1 phase, partly by studying cycling versus noncycling macrophages and partly by using cells expressing c-fms with tyrosine mutations in the intracytoplasmic region. CSF-1-mediated effects on the following signal transduction molecules in these systems will be described: PI3-kinase, myelin basic protein kinases, Erks, and STAT transcription factors.
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PMID:CSF-1 and cell cycle control in macrophages. 898 59

The human monocytic cell lines MUTZ-3 and MONO-MAC-6 express the lipopolysaccharide (LPS) receptor CD14. Paralleling the situation in peripheral blood monocytes (PBMo), recombinant human interleukin-4 (IL-4) down-regulated the expression of CD14 on the cell surface of MUTZ-3, but not that of MONO-MAC-6 cells. In addition, preincubation with IL-4 prevented the LPS-induced up-regulation of IL-1 beta mRNA levels in MUTZ-3, but not in MONO-MAC-6 cells. We examined whether the differential responsiveness of the cell lines was due to the missing expression of the IL-4 receptor (IL-4R) alpha or gamma c chain in MONO-MAC-6 cells. Flow cytometric and immunoprecipitation analysis revealed expression of both IL-4R chains in both cell lines. In addition, short-term stimulation with IL-4 induced tyrosine-phosphorylation of the gamma c chain. As both cell lines also expressed signal transducer and activator of transcription 6 (STAT 6), our data suggested that the differential reaction patterns of MUTZ-3 and MONO-MAC-6 cells were not due to a generally defective IL-4R complex. Interestingly, long-term (48 hr) treatment with LPS rendered MONO-MAC-6 cells sensitive to IL-4. LPS up-regulated expression of monocyte-specific esterase (MSE) mRNA as well as CD14 protein in MONO-MAC-6 cells; both effects were inhibited by IL-4. This stimulation was not paralleled by an increase of IL-4R mRNA or protein expression supporting the above hypothesis of a constitutively present and active IL-4R. We discuss possible causes for the differential reaction patterns of MUTZ-3 and MONO-MAC-6 cells to IL-4.
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PMID:MUTZ-3, a monocytic model cell line for interleukin-4 and lipopolysaccharide studies. 901 29

This study was designed to investigate the presence of IgG1 alloreactive memory cells in the peripheral blood in humans and their in vitro activation requirements. Alloreactive antibody production was measured after cell activation with cytokines: Interleukin (IL) 2, IL-4 and IL-10, interferon gamma, alloantigens and/or OKT3, lipopolysaccharide or Pokeweed mitogen and Epstein-Barr virus transformation. The examined cells were taken from ten sensitized and five nonsensitized uremic patients with previous graft loss and five normal controls. The titers and percentage panel reactive IgG1 antibody reactivity present in the respective sera was further compared with the in vitro profile. Alloreactive antibody reactivity was measured by PRA-STAT ELISA method. The results show that: 1) Short term control T cell lines or nonsensitized cells were unable to provide the necessary help to autologous B cells to produce alloreactive antibodies of the IgG subclass. 2) Activated cells from sensitized patients produced low levels of alloreactive IgGl antibodies. 3) Stimulation with any of the cytokines and/or mitogens or alloantigens or allopeptides was not sufficient to produce consistent levels of alloreactive IgG 1 antibodies, in spite of its presence in the respective sera.
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PMID:In vitro IgG1 alloreactive antibody production by circulating memory cells in humans. 971 Mar 43

STAT6, NF-kappaB (p50) and C/EBPbeta transcription factors (TF) were examined with respect to CD23 regulation. Electrophoretic mobility shift assay (EMSA), competition and supershift analysis demonstrated that STAT6 binds the CD23a promoter but with a lower affinity than the consensus site. STAT6-/- mice were analyzed for CD23 levels and showed reduced expression after CD40 ligand trimer (CD40LT) stimulation. However, normal CD23 expression and even some IgE production was induced in STAT6-/- mice with CD40LT/IL-4. EMSA analysis indicated that the CD23a STAT site was bound by a protein in nuclear extracts from CD40+/-IL-4-stimulated STAT6-/-B cells. Western blot analysis of these nuclear extracts demonstrated the presence of STAT3 and STAT5, suggesting that these STATs can induce CD23 in this situation. Further supporting evidence was obtained by showing that IL-2 and IL-4 both synergize with CD40 in an identical manner for CD23 induction on STAT6-/- B cells. EMSA analysis of the two putative NF-kappaB sites confirmed binding to both, although one site bound with a higher affinity than the second. Analysis of p50-/-mice indicated that this subunit was not necessary for CD23 induction or CD40/IL-4-induced IgE production. Finally, no role for C/EBP was observed in CD23 induction by EMSA or by CD23 induction analysis in C/EBPbeta-/- mice, whereas the absence of C/EBP, did have an effect on IgE production and lipopolysaccharide-induced B cell proliferation. Based on these data, a model is presented which suggests that CD23 superinduction results from STAT and NF-kappaB interaction.
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PMID:STAT6, NF-kappaB and C/EBP in CD23 expression and IgE production. 979 20

Inducible nitric oxide synthase (iNOS) is induced in many cell types by cytokines and lipopolysaccharide (LPS). Cytokine signal transduction is believed to be mediated primarily through the JAK/STAT pathway. We therefore examined the effects of a JAK2-specific inhibitor, an antisense oligonucleotide to JAK2, and electroporation of neutralizing anti-STAT1 and anti-STAT3 antibodies on IFNgamma- and LPS-stimulated induction of iNOS in vascular smooth muscle cells. Unexpectedly, we found that the JAK/STAT pathway suppresses IFNgamma- and LPS-stimulated iNOS induction in these cells. In contrast, the JAK/STAT pathway appears to have a positive role in iNOS induction in RAW 264.7 macrophages.
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PMID:Inhibition by the JAK/STAT pathway of IFNgamma- and LPS-stimulated nitric oxide synthase induction in vascular smooth muscle cells. 982 61

When given in the presence of gamma interferon (IFN-gamma), otherwise nontoxic doses of lipopolysaccharide (LPS or endotoxin) become highly lethal for mice. The mechanisms of this synergistic toxicity are not known. We considered the possibility that an interaction between the LPS-induced NF-kappaB and IFN-gamma-induced JAK-STAT pathways at the pretranscriptional level may enhance the LPS-induced signals. To test this hypothesis, we incubated murine macrophage RAW 264.7 cells with IFN-gamma for 2 h before addition of different doses of LPS. Consistent with the synergistic induction of inducible nitric oxide synthase mRNA and nitric oxide production by a combination of LPS and IFN-gamma, IFN-gamma strongly augmented LPS-induced NF-kappaB activation and accelerated the binding of NF-kappaB to DNA to as early as 5 min. In agreement with this, IFN-gamma pretreatment promoted rapid degradation of IkappaB-alpha but not that of IkappaB-beta. Inhibition of protein synthesis during IFN-gamma treatment suppressed LPS-initiated NF-kappaB binding. A rapidly induced protein appeared to be involved in IFN-gamma priming. Preincubation of cells with antibodies to tumor necrosis factor alpha or the interleukin-1 receptor partially reduced the priming effect of IFN-gamma. In a complementary manner, LPS enhanced the activation of signal-transducing activator of transcription 1 by IFN-gamma. These data suggest novel mechanisms for the synergy between IFN-gamma and LPS by which they cross-regulate the signal-transducing molecules. Through this mechanism, IFN-gamma may transform a given dose of LPS into a lethal stimulus capable of causing sepsis. It may also serve a beneficial purpose by enabling the host to respond quickly to relatively low doses of LPS and thereby activating antibacterial defenses.
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PMID:Gamma interferon augments macrophage activation by lipopolysaccharide by two distinct mechanisms, at the signal transduction level and via an autocrine mechanism involving tumor necrosis factor alpha and interleukin-1. 986 17

The antitumor agents flavone-8-acetic acid (FAA) and its dose-potent analogue 5,6-dimethylxanthenone-4-acetic acid (DMXAA), currently in clinical trials, have a novel mechanism of action that is mediated through their ability to induce a spectrum of cytokines. Since NFkappaB and STAT transcription factors participate in the regulation of a number of genes involved in immune and cytokine responses, we investigated whether these transcription factors were activated in the ANA-1 murine macrophage cell line by DMXAA and FAA compared with lipopolysaccharide (LPS), a bacterial component that induces an overlapping spectrum of cytokines. Activation of STAT1 and STAT3 was observed distinctly 4 hr after DMXAA and FAA stimulation. DMXAA and FAA induced NFkappaB translocation with slower kinetics of activation compared with LPS. STAT activation by DMXAA and FAA was inhibited by cycloheximide, indicating a requirement for de novo protein synthesis. The ANA-1 cells produced high titres of interferons (IFNs) in the culture supernatant after stimulation with DMXAA and FAA, and the addition of antibodies to IFNalpha/beta inhibited STAT activation, indicating that IFNs mediated STAT activation. NFkappaB activation, on the other hand, was not inhibitable with cycloheximide or with antibodies to IFNalpha/beta. NFkappaB activation appeared to be a direct action of the anticancer agents, whereas activation of the STAT proteins was due, in part, to the high titres of IFNs induced. These results demonstrate the significance of the IFN response in initiating the cascade of secondary events that may contribute to the overall antitumor efficacy of DMXAA and FAA in murine models.
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PMID:Induction of STAT and NFkappaB activation by the antitumor agents 5,6-dimethylxanthenone-4-acetic acid and flavone acetic acid in a murine macrophage cell line. 1048 75

We have recently shown that, in human neutrophils, interleukin-10 (IL-10) fails to induce specific DNA-binding activities to the gamma-interferon response region (GRR), a regulatory element located in the FcgammaRI gene promoter, which is required for transcriptional activation by IL-10 and interferon gamma (IFNgamma) in monocytic cells. In this study, we report that IL-10 is also unable to induce the binding of STAT1 or STAT3 to the serum-inducible element (hSIE/m67), despite the fact that both proteins are expressed in neutrophils. Whereas IFNgamma and granulocyte colony-stimulating factor (G-CSF) are efficient inducers of STAT1 and STAT3 tyrosine phosphorylation in polymorphonuclear neutrophils (PMN), IL-10 fails to trigger STAT1 and STAT3 tyrosine and serine phosphorylation, therefore explaining its inability to induce the FcgammaRI expression in these cells. By contrast, we demonstrate that IL-10 alone represents an efficient stimulus of CIS3/SOCS3 mRNA expression in neutrophils. CIS3/SOCS3 belongs to the recently cloned cytokine-inducible SH2-containing protein (CIS) gene family (which also includes CIS1, CIS2, CIS4, CIS5, and JAB) that is believed to be, at least in part, under the control of STAT transcription factors and whose products are potential modulators of cytokine signaling. Moreover, IL-10 synergizes with lipopolysaccharide (LPS) in upregulating CIS3/SOCS3 mRNA expression in PMN through a mechanism that involves mRNA stabilization. In contrast to CIS3/SOCS3, mRNA transcripts encoding other family members are unaffected by IL-10 in neutrophils. Finally, transfection of CIS3/SOCS3 in murine M1 myeloid cells suppresses LPS-induced growth arrest, macrophage-like differentiation, and nitric oxide synthesis, but not IL-6 mRNA expression. Collectively, our data suggest that, in neutrophils, the activation of STAT1 and STAT3 phosphorylation is neither required for CIS3/SOCS3 induction by IL-10 nor involved in the regulatory effects of IL-10 on cytokine production.
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PMID:Interleukin-10 (IL-10) selectively enhances CIS3/SOCS3 mRNA expression in human neutrophils: evidence for an IL-10-induced pathway that is independent of STAT protein activation. 1051 92


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