Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lung innate immune response to lipopolysaccharide (LPS) coordinates cellular inflammation, mediator, and protease release essential for host defense but deleterious in asthma, chronic obstructive pulmonary disease, and cystic fibrosis. In vitro, LPS signals to the transcription factors NFkappaB via TLR4, MyD88, and IL-1R-associated kinase (IRAK), to AP-1 by mitogen-activated protein (MAP) kinases, and via an alternate route in IRAK-deficient mice, but the in vivo lung signaling pathway(s) are not understood. We investigated the role of Akt and Erk1/2 as LPS intensely stimulates granulocyte/macrophage-colony-stimulating factor (GM-CSF) release, and neutralizing GM-CSF profoundly suppressed LPS-induced inflammation, suppressed expression and activity of lung proteases, significantly reduced GM-CSF and tumor necrosis factor alpha (TNFalpha) mRNA expression, and dampened nuclear localization of both NFkappaB (p50/65) and AP-1. LPS markedly activated Akt and Erk1/2, but not p38, in a GM-CSF-dependent manner in direct temporal association with NFkappaB and AP-1 activation. Pharmacological inhibition of Akt or Erk activation in LPS-treated tracheal explants ex vivo inhibited the release of GM-CSF. These data implicate GM-CSF-dependent activation of Akt in the amplification of this response and demonstrate the role of Erks rather than p38 in lung LPS inflammatory responses. Inhibition of GM-CSF may be of therapeutic benefit in inflammatory diseases in which LPS contributes to lung damage.
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PMID:Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFkappa B and AP-1 in vivo. 1220 54

Virus infection of susceptible cells activates multiple signaling pathways that orchestrate the activation of genes, such as cytokines, involved in the antiviral and innate immune response. Among the kinases induced are the mitogen-activated protein (MAP) kinases, Jun-amino terminal kinases (JNK) and p38, the IkappaB kinase (IKK) and DNA-PK. In addition, virus infection also activates an uncharacterized VAK responsible for the C-terminal phosphorylation and subsequent activation of interferon regulatory factor 3 (IRF-3). Virus-mediated activation of IRF-3 through VAK is dependent on viral entry and transcription, since replication deficient virus failed to induce IRF-3 activity. The pathways leading to VAK activation are not well characterized, but IRF-3 appears to represent a novel cellular detection pathway that recognizes viral nucleocapsid (N) structure. Recently, the range of inducers responsible for IRF-3 activation has increased. In addition to virus infection, recognition of bacterial infection mediated through lipopolysaccharide by Toll-like receptor 4 has also been reported. Furthermore, MAP kinase kinase kinase (MAP KKK)-related pathways and DNA-PK induce N-terminal phosphorylation of IRF-3. This review summarizes recent observations in the identification of novel signaling pathways leading to IRF-3 activation.
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PMID:Multiple signaling pathways leading to the activation of interferon regulatory factor 3. 1221 96

The anti-inflammatory effect of FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5,1-c][1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate), a p38 mitogen-activated protein (MAP) kinase inhibitor, was examined in two mouse models of acute inflammation. Carrageenan-induced paw edema was inhibited by pretreatment with FR167653, anti-tumor necrosis factor (TNF)-alpha antibody, and NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide), a selective cyclooxygenase-2 inhibitor. Carrageenan increased TNF-alpha and prostaglandin E(2) levels in the paw, both of which were suppressed by FR167653. Subcutaneous injection of lipopolysaccharide at the back of mouse caused local increase in vascular permeability determined by leakage of Pontamine sky blue. FR167653 dose-dependently inhibited the lipopolysaccharide-induced plasma leakage. FR167653 also inhibited lipopolysaccharide-induced increases in serum TNF-alpha level, and skin TNF-alpha and prostaglandin E(2) levels at the injection site. On the other hand, FR167653 did not reduce arachidonic acid-induced plasma leakage which is not mediated by cyclooxygenase-2. FR167653 exhibits anti-inflammatory effects against both carrageenan-induced paw edema and lipopolysaccharide-induced plasma leakage through inhibiting the synthesis of inflammatory mediators that are regulated by p38 MAP kinase.
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PMID:Anti-inflammatory potency of FR167653, a p38 mitogen-activated protein kinase inhibitor, in mouse models of acute inflammation. 1224 95

This study was designed to systemically investigate the kinetics of extracellular signal-regulated kinase (ERK) 1/2, p54 c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) in lipopolysaccharide (LPS)-stimulated Kupffer cells (KC) simultaneously at the levels of protein expression, phosphorylation, and kinase activity, respectively, and their role in mediating pro- and anti-inflammatory cytokines. The protein expression, phosphorylation, and activities of these MAPKs in LPS-stimulated primary mouse KCs were determined with SDS-PAGE and western blotting using nonphosphorylated or phosphospecific antibodies or their corresponding substrates. The levels of TNF-alpha and IL-10 in culture supernatants were measured with ELISA kits. The results revealed that LPS stimulation, although not up- or downregulating the protein expression of ERK1/2, p54JNK, and p38 MAPKs in KCs, could induce rapid and significant activation of these kinases, with parallel profiles of changes in both phosphorylation and kinase activities. Although ERK1/2, p54JNK, and p38 kinases in LPS-stimulated KCs have similar kinetics of activation, the activation of ERK1/2 and p38 kinases was the most prominent. Inhibition of p38 MAPK with SB203580 inhibited the production of TNF-alpha and IL-10 by LPS-stimulated KCs, whereas blockade of ERK1/2 with PD98059 could reduce TNF-alpha production, but did not affect IL-10 production. Furthermore, PD98059 and SB203580 had an additive effect on TNF-alpha production, but PD98059 did not augment the SB203580-induced inhibition of IL-10 production. These data indicate that LPS stimulation, although not inducing any change in protein expression, results in rapid activation of ERK1/2, p54JNK, and p38 kinases in KCs, and that they may have different importance in the regulation of pro- and anti-inflammatory responses by LPS-stimulated KCs.
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PMID:Kinetics of mitogen-activated protein kinase family in lipopolysaccharide-stimulated mouse Kupffer cells and their role in cytokine production. 1239 77

Interleukin (IL)-1 is an important mediator of acute brain injury and inflammation, and has been implicated in chronic neurodegeneration. The main source of IL-1 in the CNS is microglial cells, which have also been suggested as targets for its action. However, no data exist demonstrating expression of IL-1 receptors [IL-1 type-I receptor (IL-1RI), IL-1 type-II receptor (IL-1RII) and IL-1 receptor accessory protein (IL-1RAcP)] on microglia. In the present study we investigated whether microglia express IL-1 receptors and whether they present target or modulatory properties for IL-1 actions. RT-PCR analysis demonstrated lower expression of IL-1RI and higher expression of IL-1RII mRNAs in mouse microglial cultures compared with mixed glial or pure astrocyte cultures. Bacterial lipopolysaccharide (LPS) caused increased expression of IL-1RI, IL-1RII and IL-1RAcP mRNAs, induced the release of IL-1beta, IL-6 and prostaglandin-E2 (PGE2), and activated nuclear factor kappaB (NF-kappaB) and the mitogen-activated protein kinases (MAPKs) p38, and extracellular signal-regulated protein kinase (ERK1/2), but not c-Jun N-terminal kinase (JNK) in microglial cultures. In comparison, IL-1beta induced the release of PGE2, IL-6 and activated NF-kappaB, p38, JNK and ERK1/2 in mixed glial cultures, but failed to induce any of these responses in microglial cell cultures. IL-1beta also failed to affect LPS-primed microglial cells. Interestingly, a neutralizing antibody to IL-1RII significantly increased the concentration of IL-1beta in the medium of LPS-treated microglia and exacerbated the IL-1beta-induced IL-6 release in mixed glia, providing the first evidence that microglial IL-1RII regulates IL-1beta actions by binding excess levels of this cytokine during brain inflammation.
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PMID:Expression of interleukin-1 receptors and their role in interleukin-1 actions in murine microglial cells. 1242 47

Signal transduction through Toll-like receptors (TLRs) originates from their intracellular Toll/interleukin-1 receptor (TIR) domain, which binds to MyD88, a common adaptor protein containing a TIR domain. Although cytokine production is completely abolished in MyD88-deficient mice, some responses to lipopolysaccharide (LPS), including the induction of interferon-inducible genes and the maturation of dendritic cells, are still observed. Another adaptor, TIRAP (also known as Mal), has been cloned as a molecule that specifically associates with TLR4 and thus may be responsible for the MyD88-independent response. Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. As in MyD88-deficient mice, LPS activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases is induced with delayed kinetics in TIRAP-deficient mice. Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice; they also show defective response to TLR2 ligands, but not to stimuli that activate TLR3, TLR7 or TLR9. In contrast to previous suggestions, our results show that TIRAP is not specific to TLR4 signalling and does not participate in the MyD88-independent pathway. Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4.
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PMID:Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. 1244 41

Mammalian Toll-like receptors (TLRs) function as sensors of infection and induce the activation of innate and adaptive immune responses. Upon recognizing conserved pathogen-associated molecular products, TLRs activate host defence responses through their intracellular signalling domain, the Toll/interleukin-1 receptor (TIR) domain, and the downstream adaptor protein MyD88 (refs 1-3). Although members of the TLR and the interleukin-1 (IL-1) receptor families all signal through MyD88, the signalling pathways induced by individual receptors differ. TIRAP, an adaptor protein in the TLR signalling pathway, has been identified and shown to function downstream of TLR4 (refs 4, 5). Here we report the generation of mice deficient in the Tirap gene. TIRAP-deficient mice respond normally to the TLR5, TLR7 and TLR9 ligands, as well as to IL-1 and IL-18, but have defects in cytokine production and in activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases in response to lipopolysaccharide, a ligand for TLR4. In addition, TIRAP-deficient mice are also impaired in their responses to ligands for TLR2, TLR1 and TLR6. Thus, TIRAP is differentially involved in signalling by members of the TLR family and may account for specificity in the downstream signalling of individual TLRs.
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PMID:The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. 1244 42

The mechanisms by which lipopolysaccharide (LPS) is recognized, and how such recognition leads to innate immune responses, are poorly understood. Stimulation with LPS induces the activation of a variety of proteins, including mitogen-activated protein kinases (MAPKs) and NF-kappaB. Activation of protein tyrosine kinases (PTKs) is also necessary for a number of biological responses to LPS. We used a murine macrophage-like cell line, RAW264.7, to demonstrate that Janus kinase (JAK)2 is tyrosine phosphorylated immediately after LPS stimulation. Anti-Toll-like receptor (TLR)4 neutralization antibody inhibits the phosphorylation of JAK2 and the c-Jun NH2-terminal protein kinase (JNK). Both the JAK inhibitor AG490 and the kinase-deficient JAK2 protein reduce the phosphorylation of JNK and phosphatidylinositol 3-kinase (PI3K) via LPS stimulation. Pharmacological inhibition of the kinase activity of PI3K with LY-294002 decreases the phosphorylation of JNK. Finally, we show that JAK2 is involved in the production of IL-1beta and IL-6. PI3K and JNK are also important for the production of IL-1beta. These results suggest that LPS induces tyrosine phosphorylation of JAK2 via TLR4 and that JAK2 regulates phosphorylation of JNK mainly through activation of PI3K. Phosphorylation of JAK2 via LPS stimulation is important for the production of IL-1beta via the PI3K/JNK cascade. Thus JAK2 plays a pivotal role in LPS-induced signaling in macrophages.
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PMID:Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages. 1268 12

In the present study, we investigated the effects and mechanisms of a novel potent antioxidant, octyl caffeate, on the induction of iNOS expression by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) in cultured primary rat aortic smooth muscle cells (RASMCs) in vitro and LPS-induced hypotension in vivo. Octyl caffeate (0.1-1.0 microM) exerted a concentration-dependent inhibition of iron-catalyzed lipid peroxidation in rat brain homogenates. Furthermore, octyl caffeate (20, 50, and 100 microM) concentration-dependently diminished the initial rate of superoxide-induced NBT reduction and the enzymatic activity of xanthine oxidase. It also concentration-dependently (1-50 microM) inhibited the NO production, iNOS protein and messenger RNA expressions upon stimulation by LPS (100 microg/mL)/IFN-gamma (100U/mL) in RASMCs. In addition, we found that octyl caffeate did not significantly affect IkappaBalpha degradation stimulated by LPS/IFN-gamma in RASMCs. On the other hand, octyl caffeate (10 and 50 microM) significantly suppressed activation of c-Jun-N-terminal kinase and extracellular signal-regulated kinase. Moreover, octyl caffeate (10mg/kg, i.v.) significantly inhibited the fall in mean arterial pressure stimulated by LPS (7.5mg/kg) in rats. In conclusion, we demonstrate that a novel potent antioxidant, octyl caffeate, significantly ameliorates circulatory failure of endotoxemia in vivo by a mechanism involving suppression of iNOS expression through inactivation of mitogen-activated protein kinases in RASMCs.
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PMID:A novel antioxidant, octyl caffeate, suppression of LPS/IFN-gamma-induced inducible nitric oxide synthase gene expression in rat aortic smooth muscle cells. 1269 79

Whether deletion of tumor necrosis factor (TNF) receptor 1 or 2 affects lipopolysaccharide (LPS)-mediated signaling is not understood. In this report, we used macrophages derived from wild type (wt) mice and from mice null for the type 1 receptor (p60-/-), the type 2 receptor (p80-/-), or both (p60-/- p80-/-) to investigate the effect of these receptors on LPS-mediated activation of NF-kappaB, mitogen-activated protein kinases, and apoptosis. LPS activated NF-kappaB by 3-4-fold in wt cells but by 9-10-fold in p60-/-, p80-/-, and p60-/- p80-/- macrophages. These results correlated with the IkappaBalpha kinase activation, which is needed for NF-kappaB activation. LPS-induced cyclooxygenase-2 and inducible NO synthase proteins and NO production were maximum in p60-/- p80-/- macrophages and minimum in wt cells. LPS activated C-Jun N-terminal kinase, p38MAPK, and extracellular signal-regulated kinase in wt cells, but the levels were much higher in p60-/-, p80-/-, and p60-/- p80-/- cells. LPS-induced cytotoxicity, poly(ADP-ribose) polymerase cleavage, and annexin V staining were also highest in p60-/- p80-/- cells and lowest in wt cells. The difference in LPS signaling was unrelated to the expression of LPS receptors, CD14, or toll-like receptor 4. Overall, our studies indicate that deletion of either of the TNF receptors sensitizes the macrophages to LPS and provide evidence for cross-talk between TNF and LPS signaling.
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PMID:Genetic deletion of the tumor necrosis factor receptor p60 or p80 sensitizes macrophages to lipopolysaccharide-induced nuclear factor-kappa B, mitogen-activated protein kinases, and apoptosis. 1269 14


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