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)

Inflammation and catabolism in response to trauma, surgery, critical illness or bacteria lead to a compromise of essential organs, which can lead to prolonged clinical stay and even death. Mediators responsible for catabolism were thought to be proinflammatory cytokines, but recently the focus has shifted to signal transduction. The purpose of the present study was to determine differences between two pathophysiologic states, sepsis and thermal injury, in signal transduction and cytokine expression and thus define the importance of the signal transcription pathway. Rats were randomly divided to either receive lipopolysaccharide (3 mg/kg body weight or a 30% total body surface area burn) or they received no treatment and served as controls. Animals were sacrificed 1, 2, 5, and 7 days postinsult and serum and liver harvested for analysis. A thermal injury appeared to have a slow release and expression of signal transcription factors and cytokines and a sepsis showed a rapid increase of mediators and also a fast decrease. The changes in cytokine profiles after burn, particularly interleukin-1beta and macrophage inhibitory factor, appear to be mediated by C/EBP-beta and STAT-3, whereas after the induction of a sepsis, tumor necrosis factor and interleukin-6 are mainly mediated by STAT-5. Based on our findings we suggest that the pathophysiologic state of a thermal injury is not comparable with sepsis in association with signal transcription factors and the differences in intracellular and extracellular signaling therefore opens new ideas for therapeutic options.
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PMID:Differences in the hepatic signal transcription pathway and cytokine expression between thermal injury and sepsis. 1462 78

Expression of stem cell antigen-1 (Ly-6A/E) is developmentally regulated in murine B cells. However, little is known about its modulation during B cell activation. We report here the differential regulation of Ly-6A/E expression in response to diverse activation signals in mature B cells. Stimulation of resting B cells through the antigen receptor (BCR) inhibited, Ly-6A/E surface expression in dose dependent manner. Activation induced downregulation of Ly-6A/E is specific to BCR mediated signaling events as stimulation of B cells with anti-CD40, lipopolysaccharide or interferon-gamma induced upregulation of Ly-6A/E surface expression. The activation induced differential modulation of Ly-6A/E expression is mediated at the mRNA levels. A role for BCR signaling in inhibition of Ly-6A/E expression was further confirmed using STAT-1(-/-) B cells, which expressed constitutive, but not inducible Ly-6A/E. The BCR induced inhibition of Ly-6A/E RNA and surface expression was mimicked by ionomycin, but not phorbol myristate acetate, indicating a role for calcium but not protein kinase C dependent signaling events. Inhibition of calcineurin reversed the BCR or ionomycin inhibited Ly-6A/E expression. Interestingly, in vitro differentiation analysis of Ly-6A/E(+) and Ly-6A/E(-) splenic B cells revealed the Ly-6A/E(+) cells to be the major source of antibody production, suggesting a potential role for Ly-6A/E in B cell differentiation. These studies provide the first evidence for activation induced differential modulation and differentiation of Ly-6A/E(+) B cells.
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PMID:Activation induced differential regulation of stem cell antigen-1 (Ly-6A/E) expression in murine B cells. 1464 3

Since macrophages (Mphis) are a first line of defense against pathogens, and are involved in both innate and adaptive immunity, understanding the impact of aging on Mphi function is important. In the past studies, we and others have shown that aging decreases Mphi responsiveness to classical activating signals (e.g. IFN-gamma and lipopolysaccharide, LPS). In this study, we examined the impact of aging on Mphi signaling through the IFN-gamma receptor pathway. Mphis from male Balb/c mice aged 2 (young) and 18-24 (old) months were purified and then stimulated with IFN-gamma. Western blotting revealed a significant reduction ( approximately 50%) in IFN-gamma-stimulated tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT-1) alpha and beta in Mphis from aged, when compared with young mice. This reduction in phospho-STAT-1 was associated with a significant constitutive reduction ( approximately 80%) in total STAT-1alpha protein and a complete inhibition of STAT-1 gene expression in response to IFN-gamma in old compared to young mice. These data may, in part, explain why classical Mphi responses like reactive nitrogen and oxygen species generation, tumor killing and microbicidal activity are lower in Mphis from aged subjects. We conclude that peritoneal Mphis from aged mice have an intrinsic defect in Jak-STAT signaling which prevents them from fully responding to IFN-gamma.
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PMID:Macrophage hypo-responsiveness to interferon-gamma in aged mice is associated with impaired signaling through Jak-STAT. 1503 19

The mechanism of glutamine (Gln)-mediated down-regulation of inflammation in the intestine is poorly understood. We hypothesize that Gln down-regulates lipopolysaccharide (LPS)-stimulated IL-8 production in intestinal epithelial cells via transcription factors that counteract the effect of LPS-mediated increase in IL-8. Caco-2 cells were incubated with different doses of Gln with or without methionine sulfoximine (MS), an inhibitor of glutamine synthetase for 24 h before stimulation by LPS (100 microg/ml for 24 h). Inhibitors of the mitogen activated protein kinase (MAPK) family were added to cells for 1.5 h following stimulation by LPS. The p38 inhibitor SB 203580 resulted in a significant decrease in IL-8 peptide production (p < 0.01). However, p38 MAPK activity increased with Gln (p < 0.05), suggesting that this was not involved with Gln-mediated down-regulation of IL-8. Screening of 54 transcription factors demonstrated that STAT-4 was the only inflammation-related transcription factor that was up-regulated by Gln depletion and down-regulated with Gln supplementation (2-fold increase), paralleling IL-8 production. EMSA analysis confirmed these findings (3.5-fold increase). These results indicate that Gln deprivation enhances IL-8 production by Caco-2 cells after LPS stimulation and that down-regulation of IL-8 production with Gln is associated with alterations in STAT-4 transcription factor binding.
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PMID:Mechanism of glutamine-mediated amelioration of lipopolysaccharide-induced IL-8 production in Caco-2 cells. 1505 Jun 5

Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is a type II C-type lectin that functions as an adhesion receptor and mediates binding and internalization of pathogens such as virus (human immunodeficiency virus, hepatitis C), bacteria (Mycobacterium), fungi, and parasites. DC-SIGN expression in vivo is primarily restricted to interstitial dendritic cells (DC) and certain tissue macrophages. We now report that leukemic THP-1 cells, widely used as a model for monocyte-macrophage differentiation, express very low basal levels of DC-SIGN and that DC-SIGN expression in THP-1 cells is regulated during differentiation. Differentiation-inducing agents (phorbol ester, bryostatin) conveyed THP-1 cells with the ability to up-regulate DC-SIGN mRNA levels and cell surface expression in response to interleukin-4 (IL-4) or IL-13. DC-SIGN up-regulation required a functional JAK-STAT signaling pathway, was inhibited in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha), and conferred THP-1 cells with increased pathogen recognition and T cell stimulatory capabilities. The up-regulation of DC-SIGN on THP-1 cells resembles its inducible expression on monocytes and macrophages, where DC-SIGN expression is also induced by IL-4/IL-13 and negatively regulated by TNF-alpha, LPS, and vitamin D(3). These results point to THP-1 cells as a useful cellular system to characterize the pathogen-binding capabilities of DC-SIGN and to dissect the molecular mechanisms that control its regulated and tissue-specific expression in myeloid dendritic cells, and the results suggest that DC-SIGN constitutes a marker for both DC and alternatively activated macrophages.
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PMID:Regulated expression of the pathogen receptor dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin in THP-1 human leukemic cells, monocytes, and macrophages. 1507 Sep 1

Our previous study indicated that the interleukin (IL)-6/STAT-3 signal was up-regulated in inflammatory bowel disease (IBD) in both humans and animal models. We also discovered phosphorylated STAT-3 in the nucleus of the colonic epithelial cells in IBD mice. Intestinal epithelial cells (IEC) have been shown to secrete IL-6. Therefore, the secretion of IL-6 from IEC may be one of the mechanisms of STAT-3 phosphorylation in IEC during the pathogenesis of IBD, and inhibition of IL-6 production by IEC may be beneficial in preventing IBD. We examined the preventative effect of various types of fucoidans on IL-6 production in a lipopolysaccharide (LPS)-stimulated murine colonic epithelial cells line, CMT-93, in vitro. We also determined in vivo the effect of fucoidans on murine chronic colitis induced with dextran sodium sulphate. Among fucoidans, those from Cladosiphon okamuranus Tokida and Kjellmaniella crassifolia inhibited IL-6 production in CMT-93 cells with the down-regulation of NF-kappaB nuclear translocation. Analysis of the effect of fucoidan on murine colitis in vivo showed that the disease activity index and myeloperoxidase activity decreased in mice fed Cladosiphon fucoidan, but not Fucus fucoidan. Cytokine profiles in colonic lamina propria indicated that the synthesis of interferon (IFN)-gamma and IL-6 decreased and that of IL-10 and transforming growth factor (TGF)-beta increased in mice fed Cladosiphon fucoidan, compared with mice fed a standard diet or Fucus fucoidan. The levels of IL-6 mRNA in colonic epithelial cells was lower in colitis-induced Balb/c mice fed Cladosiphon fucoidan than those fed a standard diet. Fucoidan improves murine chronic colitis by down-regulating the synthesis of IL-6 in the colonic epithelial cells. Fucoidan derived from C. o. Tokida may be useful as a dietary substance for the patients with inflammatory bowel disease.
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PMID:Fucoidan derived from Cladosiphon okamuranus Tokida ameliorates murine chronic colitis through the down-regulation of interleukin-6 production on colonic epithelial cells. 1514 44

Astrocytes and microglia, the two immune-regulatory cells of the central nervous system (CNS), are activated by a variety of pathogens and cytokines to elicit rapid transcriptional responses. This program of activation is initiated by a set of intracellular signaling cascades that includes mitogen-activated protein kinase (MAPK), nuclear factor (NF) kappaB, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. This study defines the critical role that NADPH oxidase(Phox)-derived reactive oxygen species (ROS) play in lipopolysaccharide (LPS)- and interferon (IFN)gamma-induced signaling cascades leading to gene expression in glial cells. Treatment of rat microglia and astrocytes with LPS and IFNgamma resulted in a rapid activation of Phox and the release of ROS followed by an induction of inducible nitric oxide synthase (iNOS) expression. iNOS induction was blocked by inhibitors of Phox, i.e., diphenylene iodonium chloride (DPI) and 4-(2-aminoethyl) benzenesulfonylfluoride (AEBSF), suggesting an involvement of ROS signaling in iNOS gene expression. Exogenous catalase but not superoxide dismutase suppressed the basal activity and completely blocked induced levels of NO/iNOS, suggesting that hydrogen peroxide is the ROS involved. Phox inhibitors and catalase also suppressed LPS/IFNgamma-induced expression of cytokines, i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)alpha and blocked LPS activation of MAP kinases (i.e., p38 MAPK, c-Jun N-terminal kinase and extracellular signal-regulated kinase), NFkappaB, and IFNgamma-induced STAT1 phosphorylation. A microglial cell line stably transfected with a mutant form of Phox subunit, i.e., p47(phox) W(193)R, and primary astrocytes derived from Phox-deficient mice showed attenuated ROS production and induction of iNOS in response to LPS/IFNgamma, further strengthening the notion that Phox-derived ROS are crucial for proinflammatory gene expression in glial cells.
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PMID:Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. 1526 24

Bacterial lipopolysaccharide (LPS) triggers innate immune responses through the Toll-like receptor (TLR) 4. Regulation of TLR signaling is a key step for inflammation, septic shock and innate/adaptive immunity. TLR signaling is shown to be regulated by cytokines, such as interferon-gamma (positive) and interleukin-10 and IL-4 (negative). However, molecular mechanisms of the regulation of LPS signaling by cytokines have not been clarified. Cytokine signaling is regulated by CIS/SOCS family proteins. Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity. We demonstrate that SOCS1 and SOCS3 play an important regulatory role in macrophages and dendritic cells (DCs) by modulating TLR signaling. SOCS1 negatively regulates not only the JAK/STAT pathway, but also the TLR-NF-kappaB pathway. SOCS3 protein was strongly induced by both IL-6 and IL-10 in the presence of LPS, but selectively inhibited IL-6 signaling. Therefore lack of SOCS3 gene in macrophages resulted in suppression of TLR signaling by hyperactivation of STAT3.
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PMID:[Regulation of cytokine and toll-like receptor signaling by SOCS family genes]. 1559 84

PKR, the double-stranded RNA (dsRNA)-activated serine/threonine kinase, has been implicated as an important component of host responses to infection and various situations of cellular stress. The involvement of PKR in signal transduction and regulation of transcription suggested to us that it may play an important role in lipopolysaccharide (LPS)-induced activation of STAT1 in rat brain immune cells. We found that LPS rapidly stimulated the phosphorylation of PKR within 5 min, followed by phosphorylation of STAT1 at 2 h in rat primary microglia and astrocyte. Using 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, and PKR-specific short interfering RNA (siRNA), we demonstrated that activation of PKR was essential for LPS-induced activation of STAT1. Inhibition of PKR activity by 2-AP resulted in suppression not only of STAT1 phosphorylation, but also of nuclear factors binding activity to GAS/ISRE elements. 2-AP also significantly suppressed the downstream events of LPS-stimulated STAT1 phosphorylation, including STAT-mediated transcriptional responses and generation of nitric oxide, a hallmark of brain inflammation. Consistent with these results, transfection of PKR-specific siRNA markedly attenuated all the STAT1 dependent inflammatory signaling responses tested. We further revealed that activation of PKR by LPS led to the induction of IFN-beta through activation of NF-kappaB, triggering the phosphorylation of STAT1 in rat brain glial cells. Taken together, these findings indicate that PKR functions as an essential modulator in LPS-induced STAT inflammatory signaling events, and provides new insight into endotoxin-induced CNS diseases following infection.
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PMID:Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells. 1563 Jul 3

Signal transducers and activators of transcription (STATs) have recently been reported to mediate glial activation, and thus potentially play important roles in many neuroinflammatory diseases. We examined the effect of peroxisome proliferator-activated receptor (PPAR) activators on inflammatory responses in cultured rat brain glial cells. Four PPAR-alpha activators were tested, three fibrates (WY14643, clofibrate and fenofibrate) and an arachidonic acid derivative (5,8,11,14-eicosatetraynoic acid). We found that all four PPAR-alpha activators suppressed lipopolysaccharide-stimulated STAT1 phosphorylation and nuclear factor binding to gamma-interferon-activated sequence/interferon-alpha-stimulated response element sites known to contain STAT binding sites. PPAR-alpha activators also suppressed lipopolysaccharide-stimulated tumor necrosis factor-alpha and monocyte chemoattractant protein-1 transcription and release. These results suggest that PPAR-alpha activators may be useful in the treatment of inflammatory brain diseases.
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PMID:PPAR-alpha activators suppress STAT1 inflammatory signaling in lipopolysaccharide-activated rat glia. 1589 79


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