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)

Tyrosine-phosphorylated signal transducer and activator of transcription 1 alpha (STAT1 alpha) is a 91-kDa protein responsible for interferon-gamma (IFN-gamma)-dependent transcription. The present study demonstrates that activation by IFN-gamma of murine macrophages resulted in tyrosine phosphorylation of STAT1 alpha identified by immunoprecipitation. The tyrosine phosphorylation of STAT1 alpha was found highly sensitive to treatment by delta-9 tetrahydrocannabinol (THC), a major marijuana component. Subsequently, the isoform formation of p91 due to tyrosine phosphorylation was reduced in THC-treated macrophages. Although inhibition by THC of the tyrosine phosphorylation of STAT1 alpha induced by IFN-gamma was in a THC concentration-related manner, the tyrosine phosphorylation of other proteins induced by lipopolysaccharide/IFN-gamma treatment of macrophages appeared insensitive to THC treatment. Our data suggest that blockade by THC of tyrosine phosphorylation of STAT1 alpha may be an important mechanism involved in the broad immunosuppressive effects of THC.
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PMID:Delta-9-tetrahydrocannabinol: an inhibitor of STAT1 alpha protein tyrosine phosphorylation. 865 47

Generation of an inflammatory response is a complex process involving multiple factors acting in parallel and in concert. Viruses, parasites, and bacteria, particularly lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, act cooperatively with the cytokine interferon (IFN)-gamma to induce many of the genes involved in inflammation. In addition, these components synergistically induce secretion of tumor necrosis factor alpha (TNF-alpha), which also synergizes strongly with IFN-gamma. The molecular mechanisms underlying the synergistic gene induction discussed in this review involve cooperative activation of transcription factors. IFN-gamma-activated signal transducer and activator of transcription 1 and interferon regulatory factor-1 function synergistically with nuclear factor kappaB activated by LPS and TNF-alpha. In addition, cross-talk between the signal transduction pathways upstream of the activation of the transcription factors contributes to generation of the synergistic action. Cooperative activity of proinflammatory agents profoundly influences the immune response to infections and the efficiency of cellular clearance mechanisms.
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PMID:Synergistic action of pro-inflammatory agents: cellular and molecular aspects. 1064 93

It has previously been reported by us that a brief prior exposure of mouse bone marrow culture-derived macrophages to bacterial lipopolysaccharide (LPS) resulted in a dramatic reduction in their ability to produce NO in response to a subsequent stimulus with either interferon-gamma (IFN-gamma) or IFN-gamma plus LPS. We show here that this brief exposure to LPS results in an impaired response to subsequently added IFN-gamma. A 2--4 h pretreatment with LPS leads to a dramatic reduction in the IFN-gamma-induced DNA-binding of the transcription factor, signal transducer and activator of transcription 1 alpha (STAT1 alpha). This loss in ability to activate STAT1 alpha temporally correlates with the LPS-induced accumulation of mRNA encoding the suppressor of cytokine signalling-1 (SOCS-1). However, LPS does not directly induce the synthesis of SOCS-1. Rather, LPS induces the synthesis of autocrine/paracrine factors that are the true mediators of SOCS-1 induction. IFN-alpha/beta is one of these mediators, but plays only a partial role in the induction of SOCS-1 because neutralization of LPS-induced IFN-alpha/beta production incompletely inhibits the induction of SOCS-1. We show that mouse IFN-beta directly induces the synthesis of SOCS-1, without the need for prior protein synthesis, and does so with faster kinetics than does LPS. Our results are consistent with the non-specific nature of LPS-induced tolerance and provide a mechanistic insight into nonspecificity; LPS indirectly induces the synthesis of a protein mediator, SOCS-1, which inhibits the signalling that is induced by IFN-gamma.
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PMID:Indirect induction of suppressor of cytokine signalling-1 in macrophages stimulated with bacterial lipopolysaccharide: partial role of autocrine/paracrine interferon-alpha/beta. 1086 Dec 16

This study examines the role of the signal transducer and activator of transcription 1 (STAT1) in induction of lipopolysaccharide (LPS)-stimulated gene expression both in vitro and in vivo. LPS-induced expression of an interferon (IFN)-inducible 10-kDa protein (IP-10), IFN regulatory factor-1 (IRF-1), and inducible nitric oxide synthase (iNOS) mRNAs was severely impaired in macrophages prepared from Stat1-/- mice, whereas levels of tumor necrosis factor alpha and KC (a C-X-C chemokine) mRNA in LPS-treated cell cultures were unaffected. A similar deficiency in LPS-induced gene expression was observed in livers and spleens from Stat1-/- mice. The reduced LPS-stimulated gene expression seen in Stat1-/- macrophages was not the result of reduced activation of nuclear factor kappaB. LPS stimulated the delayed activation of both IFN-stimulated response element and IFN-gamma-activated sequence binding activity in macrophages from wild-type mice. Activation of these STAT1-containing transcription factors was mediated by the intermediate induction of type I IFNs, since the LPS-induced IP-10, IRF-1, and iNOS mRNA expression was markedly reduced in macrophages from IFN-alpha/betaR-/- mice and blocked by cotreatment with antibodies against type I IFN. These results indicate that indirect activation of STAT1 by LPS-induced type I IFN participates in promoting optimal expression of LPS-inducible genes, and they suggest that STAT1 may play a critical role in innate immunity against gram-negative bacterial infection.
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PMID:Requirement for STAT1 in LPS-induced gene expression in macrophages. 1131 Aug 46

A general paradigm in signal transduction is ligand-induced feedback inhibition and the desensitization of signaling. We found that subthreshold concentrations of interferon-gamma (IFN-gamma), which did not activate macrophages, increased their sensitivity to subsequent IFN-gamma stimulation; this resulted in increased signal transducer and activator of transcription 1 (STAT1) activation and increased IFN-gamma#150;dependent gene activation. Sensitization of IFN-gamma signaling was mediated by the induction of STAT1 expression by low doses of IFN-gamma that did not effectively induce feedback inhibition. IFN-gamma signaling was sensitized in vivo after IFN-gamma injection, and STAT1 expression was increased after injection of lipopolysaccharide and in rheumatoid arthritis synovial cells. These results identify a mechanism that sensitizes macrophages to low concentrations of IFN-gamma and regulates IFN-gamma responses in acute and chronic inflammation.
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PMID:Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. 1217 44

Murine caspase-11, together with caspase-1, is essential for the production of IL-1beta in response to lipopolysaccharide (LPS). In most cells, caspase-11 is only expressed upon induction with pro-inflammatory stimuli. To understand how caspase-11 expression is transcriptionally regulated, we isolated the caspase-11 gene promoter by genome walking and investigated the mechanisms regulating caspase-11 gene expression in macrophages that are treated with LPS and interferon-gamma. Transient transfections with caspase-11 promoter-luciferase reporter constructs and deletion/mutation analysis revealed an essential role for NF-kappaB binding in the up-regulation of caspase-11 in response to LPS. In the case of interferon-gamma stimulation, signal transducer and activator of transcription 1 binding to the caspase-11 promoter could be shown to be required for caspase-11 expression.
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PMID:Caspase-11 gene expression in response to lipopolysaccharide and interferon-gamma requires nuclear factor-kappa B and signal transducer and activator of transcription (STAT) 1. 1219 38

The transcription factor signal transducer and activator of transcription 1 (STAT1) requires phosphorylation at both Tyr-701 and Ser-727 for full activation. IFN-gamma induces phosphorylation of both residues, whereas stress signals like UV or lipopolysaccharide stimulate phosphorylation of Ser-727 only. Using p38alpha mitogen-activated protein kinase (MAPK)-deficient cells, we show that the stress-induced phosphorylation of Ser-727 requires p38alpha MAPK activity, whereas IFN-gamma-stimulated Ser-727 phosphorylation occurs independently of the p38alpha pathway. Consistently, IFN-gamma stimulated expression of the STAT1 target gene IRF1 to a similar extent in both wild-type and p38alpha-deficient cells. However, stress-induced activation of the p38 MAPK pathway considerably enhanced the IFN-gamma-induced expression of both the endogenous IRF1 gene and a reporter driven by the IFN-gamma-activated sequence element of the IRF1 promoter. This enhancement occurred independently of increased phosphorylation of Ser-727 by the p38 pathway. Taken together, these results demonstrate an interaction between IFN-gamma signaling and the p38 pathway that leads to increased transcriptional activation by STAT1 independently of phosphorylation at Ser-727.
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PMID:p38 MAPK enhances STAT1-dependent transcription independently of Ser-727 phosphorylation. 1223 43

Bacteria-derived synthetic lipoproteins constitute potent macrophage activators in vivo and are effective stimuli, enhancing the immune response especially with respect to low or non-immunogenic compounds. N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteinyl-seryl-(lysyl)3-lysine (P3CSK4), exhibiting one of the most effective lipopeptide derivatives, represents a highly efficient immunoadjuvant in parenteral, oral, nasal and genetic immunization either in combination with or after covalent linkage to antigen. In order to further elucidate its molecular mode of action with respect to the transcriptional level, we focused our investigations on the P3CSK4-induced modulation of gene transcription. We could show that P3CSK4 activates/represses an array of at least 140 genes partly involved in signal transduction and regulation of the immune response. P3CSK4 activates the expression of tumor suppressor protein p53 (p53), c-rel, inhibitor of nuclear factor kappa B (NFkappaB) alpha (IkappaB alpha), type 2 (inducible) nitric oxide (NO) synthase (iNOS), CD40-LR, intercellular adhesion molecule-1 (ICAM-1) and interleukin 1/6/15 (IL-1/6/15). We detected no activation of heat shock protein (HSP) 27, 60, 84 and 86, osmotic stress protein 94 (Osp 94), IL-12, extracellular signal-regulated protein kinase 1 (ERK1), p38 mitogen activated protein (MAP)-kinase (p38), c-Jun NH2-terminal kinase (JNK), signal transducer and activator of transcription 1 (STAT1), CD14 and caspase genes. Furthermore, we monitored inhibition of STAT6, Janus kinase 3 (Jak3) and cyclin D1/D3 gene transcription after stimulating bone marrow-derived macrophages (BMDM) with lipopeptide. In addition, we monitored significant differences after lipopeptide and lipopolysaccharide (LPS) stimulation of bone marrow-derived murine macrophages. Our findings are of importance for further optimizing both conventional and genetic immunization, and for the development of novel synthetic vaccines.
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PMID:Lipopeptide adjuvants: monitoring and comparison of P3CSK4- and LPS-induced gene transcription. 1234 44

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

CpG DNA has immunomodulatory effects, such as the suppression of allergic responses mediated by type II T cell help (T(H)2). Here we report that CpG, but not lipopolysaccharide (LPS), rapidly induces expression of T-bet mRNA in purified B cells. Up-regulation of T-bet by CpG is abrogated in mice deficient in Toll-like receptor 9 (TLR9) and MyD88, but remains intact in B cells deficient in STAT1 (signal transducer and activator of transcription 1). Interleukin 12 (IL-12) alone does not up-regulate T-bet mRNA, but greatly enhances CpG-induced T-bet expression. Furthermore, CpG inhibits immunoglobulin G1 (IgG1) and IgE switching induced by IL-4 and CD40 signaling in purified B cells, and this effect correlates with up-regulation of T-bet. Thus, CpG triggers anti-allergic immune responses by directly regulating T-bet expression via a signaling pathway in B cells that is dependent upon TLR9, independent of interferon-gamma (IFN-gamma)-STAT1 and synergistic with IL-12.
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PMID:CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells. 1458 16


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