Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Nuclear factor (NF)-kappaB regulates a central common signaling for immunity and cell survival. Artemisolide (ATM) was previously isolated as a NF-kappaB inhibitor from a plant of Artemisia asiatica. However, molecular basis of ATM on NF-kappaB activation remains to be defined. Here, we demonstrate that ATM is a typical inhibitor of IkappaB kinase beta (IKKbeta), resulting in inhibition of lipopolysaccharide (LPS)-induced NF-kappaB activation in RAW 264.7 macrophages. ATM inhibited the kinase activity of highly purified IKKbeta and also LPS-induced IKK activity in the cells. Moreover, the effect of ATM on IKKbeta activity was completely abolished by substitution of Cys-179 residue of IKKbeta to Ala residue, indicating direct targeting site of ATM. ATM could inhibit IkappaBalpha phosphorylation in LPS-activated RAW 264.7 cells and subsequently prevent NF-kappaB activation. Further, we demonstrate that ATM down-regulates NF-kappaB-dependent TNF-alpha expression. Taken together, this study provides a pharmacological potential of ATM in NF-kappaB-dependent inflammatory disorders.
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PMID:Artemisolide is a typical inhibitor of IkappaB kinase beta targeting cysteine-179 residue and down-regulates NF-kappaB-dependent TNF-alpha expression in LPS-activated macrophages. 1766 64

The NF-kappaB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-kappaB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-alpha- and LPS-mediated NF-kappaB signaling by inactivating key signaling molecules. However, little is known about how A20 is regulated and if other molecules play a role in the termination of NF-kappaB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-kappaB and JNK activation in response to TNF-alpha, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-alpha-, IL-1- and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition of NF-kappaB activation. Thus, TAX1BP1 is pivotal for the termination of NF-kappaB and JNK signaling by functioning as an essential regulator of A20.
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PMID:Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling. 1770 91

Type I interferon gene induction relies on IKK-related kinase TBK1 and IKKepsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized. We show here that TANK/ITRAF is required for the TBK1- and IKKepsilon-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKKepsilon upon lipopolysaccharide stimulation and is also subject to lipopolysaccharide- and TBK1-IKKepsilon-mediated Lys(63)-linked polyubiquitination, a mechanism that does not require TBK1-IKKepsilon kinase activity. Thus, we have identified TANK as a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKKepsilon complexes and demonstrated that these kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase for Lys(63)-linked polyubiquitination of their scaffold protein, TANK.
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PMID:Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF. 1782 24

Chicken thrombocytes are equivalent in hemostatic function to mammalian platelets. Platelets are enucleated components of mammalian blood, while thrombocytes are nucleated blood leukocytes of chickens. Platelets and thrombocytes share characteristics that contribute to innate immunity. Experiments were conducted to determine if thrombocytes could respond in vitro to lipopolysaccharide (LPS) of Salmonella minnesota through Toll-like receptor-4 (TLR4). The aim was to activate the signal pathways leading to expression of interleukin-6 (IL-6) and inducible cyclooxygenase (COX-2) and to production of prostaglandin E2 (PGE2). Chicken thrombocytes were found to express TLR4, and LPS-induced an increase in thrombocyte mRNA expression of IL-6 and COX-2 with release of PGE2 into culture media. An increase of COX-2 and PGE2 due to LPS stimulation was inhibited by MEK1 inhibitor PD98059, but IL-6 expression was unaffected by PD98059. The IKK-2 inhibitor BMS345541 inhibited IL-6 and COX-2 with reduction of PGE2 concentrations. Therefore, the MAP kinase (MAPK) pathway activates expression of COX-2 and ultimately PGE2 production, but this pathway has little or no influence on IL-6 expression in thrombocytes. The NF-kappaB pathway also influences COX-2 expression and PGE2 production, and it is a primary activation signaling cascade for IL-6 gene expression in chicken thrombocytes. Thrombocytes represent a major component of the innate immune system of chickens in response to LPS and possibly other microbial products.
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PMID:Thrombocytes respond to lipopolysaccharide through Toll-like receptor-4, and MAP kinase and NF-kappaB pathways leading to expression of interleukin-6 and cyclooxygenase-2 with production of prostaglandin E2. 1782 13

Luteolin, a plant flavonoid, has potent anti-inflammatory properties both in vitro and in vivo. However, the molecular mechanism of luteolin-mediated immune modulation has not been fully understood. In this study, we examined the effects of luteolin on the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), as well as the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) in mouse alveolar macrophage MH-S and peripheral macrophage RAW 264.7 cells. Luteolin dose-dependently inhibited the expression and production of these inflammatory genes and mediators in macrophages stimulated with lipopolysaccharide (LPS). Semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay further confirmed the suppression of LPS-induced TNF- alpha, IL-6, iNOS and COX-2 gene expression by luteolin at a transcriptional level. Luteolin also reduced the DNA binding activity of nuclear factor-kappa B (NF-kappaB) in LPS-activated macrophages. Moreover, luteolin blocked the degradation of IkappaB-alpha and nuclear translocation of NF-kappaB p65 subunit. In addition, luteolin significantly inhibited the LPS-induced DNA binding activity of activating protein-1 (AP-1). We also found that luteolin attenuated the LPS-mediated protein kinase B (Akt) and IKK phosphorylation, as well as reactive oxygen species (ROS) production. In sum, these data suggest that, by blocking NF-kappaB and AP-1 activation, luteolin acts to suppress the LPS-elicited inflammatory events in mouse alveolar macrophages, and this effect was mediated, at least in part, by inhibiting the generation of reactive oxygen species. Our observations suggest a possible therapeutic application of this agent for treating inflammatory disorders in lung.
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PMID:Luteolin suppresses inflammation-associated gene expression by blocking NF-kappaB and AP-1 activation pathway in mouse alveolar macrophages. 1797 62

Epididymitis represents a serious threat to male fertility and usually develops following secondary bacterial infection of the epididymis such as urinary tract infections or sexually transmitted diseases. Surprisingly, very little is known about the innate host response triggered by bacterial infection in the male reproductive tract. In this study we investigated the regulation and function of Nod2 in epididymal epithelial cells following lipopolysaccharide (LPS) stimulation. The immortalized epididymal epithelial cell line PC1 (proximal caput 1) constitutively expressed Toll-like receptor 4, MD-2, CD-14 but not Nod2 messenger RNA. Lipopolysaccharide (LPS; 0.5 microg/ml) rapidly induced I kappaB phosphorylation and degradation, RelA nuclear translocation and phosphorylation, which correlated with enhanced transcriptional activity (four-fold) in PC1 cells. The LPS and lipid A rapidly (1 hr) induced Nod2 messenger RNA accumulation in a dose-dependent manner. RelA and RNApolII recruitment to the Nod2 gene promoter was enhanced in LPS-stimulated cells. Molecular blockade of nuclear factor-kappaB signalling with adenovirus 5 (Ad5) I kappaB AA or adenovirus 5 double-negative (Ad5dn) IKK beta prevented LPS-induced Nod2 gene expression. Functionally, Nod2 upregulation enhanced muramyl dipeptide (MDP) -induced tumour necrosis factor messenger RNA accumulation in PC1 cells. We conclude that epididymal epithelial cells mount an innate response following LPS exposure which leads to upregulation of Nod2 and enhanced responsiveness to the microbial product MDP. The rapid Nod2 upregulation in epididymal epithelial cells is probably part of a complex innate host response aimed at protecting the male reproductive tract from the deleterious impact of bacteria.
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PMID:Regulation and functional impact of lipopolysaccharide induced Nod2 gene expression in the murine epididymal epithelial cell line PC1. 1828 70

TRAF6, a crucial adaptor molecule in innate and adaptive immunity, contains three distinct functional domains. The C-terminal TRAF domain facilitates oligomerization and sequence-specific interaction with receptors or other adaptor proteins. In conjunction with the dimeric E2 enzyme Ubc13-Uev1A, the N-terminal RING domain of TRAF6 functions as an E3 ubiquitin (Ub) ligase that facilitates its own site-specific ubiquitination through the generation of a Lys-63-linked poly-Ub chain. This modification does not cause its proteasomal degradation but rather serves as a scaffold to activate both the IKK and stress kinase pathways. Connecting the N-and C-terminal regions, the four internal zinc finger (ZF) motifs have yet to be functionally defined. In this study, we examined the role of the ZF domains in interleukin-1, lipopolysaccharide, and RANKL signaling by reconstitution of TRAF6-deficient cells with point mutations or deletions of these ZF motifs. Although ZF domains 2-4 are dispensable for activating IKK, p38, and JNK by interleukin-1 and lipopolysaccharide, the first ZF domain together with an intact RING domain of TRAF6 is essential for activating these pathways. Furthermore, TRAF6 autoubiquitination and its interaction with Ubc13 are dependent on ZF1 and an intact RING domain. Additionally, expression of TRAF6 lacking ZF2-4 in TRAF6-deficient monocytes rescues RANKL-mediated osteoclast differentiation and LPS-stimulated interleukin-6 production. These data provide evidence for the critical role of the Ub ligase activity of TRAF6, which is coordinated via the RING domain and ZF1 to supply the necessary elements in signaling by cytokines dependent upon TRAF6.
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PMID:The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKL. 1861 13

Pterostilbene, an active constituent of blueberries, is known to possess anti-inflammatory activity and also to induce apoptosis in various types of cancer cells. Here, we investigated the inhibitory effects of pterostilbene on the induction of NO synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with lipopolysaccharide (LPS). Western blotting and real-time polymerase chain reaction (PCR) analyses demonstrated that pterostilbene significantly blocked the protein and mRNA expression of iNOS and COX-2 in LPS-induced macrophages. Treatment with pterostilbene resulted in the reduction of LPS-induced nuclear translocation of the nuclear factor-kappaB (NFkappaB) subunit and the dependent transcriptional activity of NFkappaB by blocking phosphorylation of inhibitor kappaB (IkappaB)alpha and p65 and subsequent degradation of IkappaB alpha. Transient transfection experiments using NFkappaB reporter constructs indicated that pterostilbene inhibits the transcriptional activity of NFkappaB in LPS-stimulated mouse macrophages. We found that pterostilbene also inhibited LPS-induced activation of PI3K/Akt, extracellular signal-regulated kinase 1/2 and p38 MAPK. Taken together, these results show that pterostilbene down regulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NFkappaB by interfering with the activation of PI3K/Akt/IKK and MAPK. These results have an important implication for using pterostilbene toward the development of an effective anti-inflammatory agent.
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PMID:Pterostilbene suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. 1865 26

Neutrophils are key players of innate immunity and influence inflammatory and immune reactions through the production of numerous cytokines. Interleukin-18 (IL-18) is known to stimulate several neutrophil responses, and recent evidence suggests that neutrophils might represent a source of IL-18. Here, we show that neutrophils constitutively produce both IL-18 and its antagonist, IL-18BP. Cell activation does not affect IL-18BP release but leads to an increased gene expression and secretion of IL-18, a process that depends on NF-kappaB activation. Moreover, endogenous IL-18 feeds back on the neutrophils to augment cytokine generation in lipopolysaccharide-treated cells. Accordingly, exogenous IL-18 can induce the gene expression and release of several inflammatory cytokines in neutrophils, including its own expression. We finally report that IL-18 activates the p38 MAPK, MEK/ERK, and PI3K/Akt pathways in neutrophils. The IKK cascade is also activated by IL-18, resulting in IkappaB-alpha degradation, NF-kappaB activation, and RelA phosphorylation. Accordingly, these pathways contribute to the generation of inflammatory cytokines in IL-18-stimulated neutrophils. By contrast, the phosphorylation and DNA-binding activity of various STAT proteins were not induced by IL-18. Collectively, our results unveil new interactions between IL-18 and neutrophils and further support a role for these cells in influencing both innate and adaptive immunity.
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PMID:Autocrine role of endogenous interleukin-18 on inflammatory cytokine generation by human neutrophils. 1878 Jul 64

Ginsenoside Rp1 (G-Rp1) is a ginseng saponin derivative with chemopreventive and anti-cancer activities. In this study, we examined the regulatory activity of G-Rp1 on the production of interleukin (IL)-1beta, a pro-inflammatory cytokine managing acute or chronic inflammatory diseases such as septic shock and rheumatoid arthritis, from lipopolysaccharide (LPS)-treated macrophage-like RAW264.7 cells. G-Rp1 dose-dependently inhibited IL-1beta production from LPS-treated RAW264.7 cells without altering cell viability. This compound suppressed both mRNA and protein levels of IL-1beta. In particular, this compound was found to down-regulate phosphorylation of the inhibitor of kappaB (IkappaB) kinase (IKK)/IkappaBalpha, and consequent activation of NF-kappaB, but not the activation of its upstream signaling enzymes such as mitogen-activated protein kinases (MAPK) and p85, a regulatory subunit of phosphoinositide 3-kinase (PI3K). Therefore, these results suggest that G-Rp1 may act as an inhibitor of IL-1beta production by inhibiting the NF-kappaB pathway.
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PMID:Ginsenoside Rp1, a ginsenoside derivative, blocks lipopolysaccharide-induced interleukin-1beta production via suppression of the NF-kappaB pathway. 1914 54


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