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)

1. Neutrophil priming by agents such as tumour necrosis factor-alpha, granulocyte/macrophage colony-stimulating factor and lipopolysaccharide causes a dramatic increase in the response of these cells to an activating agent; this process has been shown to be critical for neutrophil-mediated tissue injury both in vitro and in vivo. 2. The principle consequence of priming, aside from a direct effect on cell polarization, deformability and integrin/selectin expression, is to permit secretagogue-induced superoxide anion generation, degranulation and lipid mediator (e.g. leukotriene B4 and arachidonic acid) release. It is now recognized that most priming agents also serve an additional function of delaying apoptosis and hence increasing the functional longevity of these cells at the inflamed site. 3. The potential mechanisms underlying priming are discussed; current data suggest a dissociation between priming and changes in receptor number and/or affinity, G-protein expression, phospholipase C and phospholipase A2 activation and changes in intracellular Ca2+ concentration. However, more recent studies support a key role for protein tyrosine phosphorylation and enhanced phospholipase D and phosphoinositide 3-kinase activity in neutrophil priming. 4. Recent work has also revealed the potential for neutrophils to spontaneously and fully 'de-prime' after an initial challenge with platelet-activating factor. This ability of neutrophils to undergo a complete cycle of priming-de-priming (and re-priming) reveals a previously unrecognized flexibility in the control of neutrophil behaviour at an inflamed site.
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PMID:Neutrophil priming: pathophysiological consequences and underlying mechanisms. 968 67

The activation of kinases of the mitogen-activated protein kinase superfamily initiated by lipopolysaccharide (LPS) plays an important role in transducing inflammatory signals. The pathway leading to the induction of stress-activated protein kinases in macrophages stimulated with LPS was investigated. The activation of Jun N-terminal kinases (JNK) by LPS is herbimycin sensitive. Using specific inhibitors, it was shown that the pathway involves the activation of phosphoinositide 3-kinase (PI 3-K). However, in contrast to previous reports, the small GTPases Cdc42 and Rac are not required downstream of PI 3-K for JNK activation. Instead, the phosphoinositides produced by PI 3-K stimulate protein kinase C (PKC) zeta activation through PDK1. In turn, activation of this atypical PKC leads to the stimulation of phosphatidylcholine phospholipase C (PC-PLC) and acidic sphingomyelinase (ASMase). It is therefore proposed that PKCzeta regulates the PC-PLC/ASMase pathway, and it is hypothesized that the resultant ceramide accumulation mediates the activation of the SEK/JNK module by LPS.
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PMID:Lipopolysaccharide induces jun N-terminal kinase activation in macrophages by a novel Cdc42/Rac-independent pathway involving sequential activation of protein kinase C zeta and phosphatidylcholine-dependent phospholipase C. 1100 16

The haemopoietic-restricted Src homology 2-containing inositol 5'-phosphatase (SHIP) acts as a negative regulator of myeloid cell proliferation, survival and end-cell activation. It does so, at least in part, by hydrolysing the phosphoinositide 3-kinase (PI3K)-generated second messenger, PtdIns(3,4,5) P (3) (PI-3,4,5-P(3)) to PtdIns(3,4) P (2). As a result, the myeloid progenitors in SHIP-knockout mice display enhanced survival and proliferation and the mice have increased numbers of neutrophils and monocytes/macrophages. Interestingly, although SHIP is not required for mast cell or macrophage development, it restrains their differentiation since progenitors from SHIP(-/-) mice differentiate into mature mast cells and macrophages significantly faster than their wild-type counterparts. This could suggest that elevated PI-3,4,5-P(3) levels accelerate myeloid differentiation. In bone-marrow-derived mast cells, SHIP prevents degranulation by IgE alone, restrains IgE-antigen-induced degranulation and limits the production of inflammatory cytokines. On the other hand, in peritoneal macrophages, SHIP is a positive regulator of NO production, since SHIP(-/-) peritoneal macrophages produce 5-10-fold less NO than their wild-type counterparts, even though they show greater lipopolysaccharide/interferon-gamma-induced nuclear factor kappa B activation and more rapid inducible NO synthase (iNOS) generation. This is a result of 10-fold higher levels of arginase I in the SHIP(-/-) macrophages, which redirects the iNOS substrate, L-arginine, from NO to ornithine production. This suggests that the chronically elevated PI-3,4,5-P(3) levels in SHIP(-/-) mice may convert M1 (killing) macrophages, which produce NO to kill micro-organisms and tumour cells, into M2 (healing) macrophages, which produce ornithine to promote host cell growth and fibrosis.
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PMID:Role of Src homology 2-containing-inositol 5'-phosphatase (SHIP) in mast cells and macrophages. 1254 3

The emigration of leukocytes across the blood-endothelium barrier and their subsequent transmigration through the interstitium is a complex process that is vital for maintaining the efficiency of the body's innate and adaptive immunity. The chemokines, a family of low-molecular-weight chemoattractant cytokines, are well recognized to be key players in this process. However, recent investigations have highlighted an important role played by the selectin family of adhesion molecules in enhancing chemokine functions. This review summarizes the in vitro and in vivo studies that support this growing notion. It discusses chemotaxis in the context of the phosphoinositide 3-kinase and p38 mitogen-activated protein kinase pathways, and their relation to several chemoattractants (i.e., interleukin-8, leukotriene-B(4), formyl-methionyl-leucyl-phenylalanine, keratinocyte-derived cytokine, and macrophage inflammatory protein-2), the possible role played by L-selectin, and finally how chemotaxis can be altered in different inflammatory settings, such as lipopolysaccharide-mediated endotoxemia or chronic vasculitis.
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PMID:L-selectin: an emerging player in chemokine function. 1285 51

Bacterial lipopolysaccharide and other immunostimulants induce gene expression of an isoform of nitric oxide synthase (iNOS) in vascular smooth muscle cells. This process is dependent on nuclear factor-kappa B (NF-kappa B) activation. The aim of this study was to investigate whether the NF-kappa B and Akt signaling pathways converge to induce iNOS in lipopolysaccharide-stimulated vascular smooth muscle cells. Treatment of vascular smooth muscle cells with lipopolysaccharide plus interferon-gamma (LPS/IFN) caused activation of Akt and NF-kappa B. LPS/IFN caused activation of the iNOS promoter and transcription of iNOS mRNA/protein, resulting in NO production. A pharmacological inhibitor of the phosphoinositide 3-kinase (PI3K)-Akt pathway, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), inhibited phosphorylation of Akt and suppressed activation of NF-kappa B by attenuating the phosphorylation and degradation of I kappa B. LY294002 thereby inhibited LPS/IFN-induced iNOS expression and NO production. Another inhibitor of the PI3K-Akt pathway, wortmannin, also inhibited NO production in VSMC. LY294002 similarly inhibited interleukin-1 beta- or tumor necrosis factor-alpha-induced NO production. The data indicate that lipopolysaccharide or cytokine stimulation of vascular smooth muscle cells leads to activation of the PI3K-Akt pathway, which then activates the NF-kappa B pathway. Thus, the PI3K-Akt pathway controls the expression of iNOS in lipopolysaccharide- and cytokine-stimulated vascular smooth muscle cells.
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PMID:Lipopolysaccharide activates Akt in vascular smooth muscle cells resulting in induction of inducible nitric oxide synthase through nuclear factor-kappa B activation. 1464 80

Studying mononuclear phagocyte cell biology through genetic manipulation by non-viral transfection methods has been challenging due to the dual problems of low transfection efficiency and the difficulty in obtaining stable transfection. To overcome this problem, we developed a system for mediating RNA interference in monocytic cells. The p110alpha isoform of phosphoinositide 3-kinases (PI3Ks) was silenced using a lentiviral vector expressing short hairpin RNA (shRNA). This resulted in the generation of stable THP-1 and U-937 monocytic cell lines deficient in p110alpha. Notably, p110alpha was silenced without affecting levels of either the other class I(A) PI3K catalytic subunits p110beta and p110delta, or the p85alpha regulatory subunit. The role of p110alpha in mediating cell adherence was examined. Monocyte adherence induced in response to either lipopolysaccharide (LPS) or 1alpha,25-dihydroxycholecalciferol (D(3)) was blocked by the PI3K inhibitor LY294002. However, although adherence induced in response to D(3) was sensitive to silencing of p110alpha, LPS-induced adherence was not. Expression of the monocyte differentiation marker CD11b was also induced by D(3) in a PI3K-dependent manner and gene silencing using shRNA showed that p110alpha was also required for this effect. Taken together, these findings demonstrate that LPS and D(3) use distinct isoforms of class I(A) PI3K to induce functional responses and that lentiviral-mediated delivery of shRNA is a powerful approach to study monocyte biology.
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PMID:Stable gene silencing in human monocytic cell lines using lentiviral-delivered small interference RNA. Silencing of the p110alpha isoform of phosphoinositide 3-kinase reveals differential regulation of adherence induced by 1alpha,25-dihydroxycholecalciferol and bacterial lipopolysaccharide. 1467 55

Primary cultures of guinea pig gastric mucosal cells express NADPH oxidase 1 (Nox1), a homolog of gp91(phox), and produce superoxide anion (O2-) at a rate of approximately 100 nmol.mg protein(-1).h(-1) in response to Helicobacter pylori (H. pylori) lipopolysaccharide (LPS) from virulent type I strains. The upregulated O2- production also enhances H. pylori LPS-stimulated tumor necrosis factor-alpha or cyclooxygenase-2 mRNA expression, which suggests a potential role for Nox1 in the pathogenesis of H. pylori-associated diseases. The H. pylori LPS-stimulated O2- production in cultured gastric mucosal cells was inhibited by actinomycin D as well as cycloheximide, suggesting that the induction is regulated at the transcriptional level. The LPS treatment not only increased the Nox1 mRNA to a greater extent but also induced expression of the message-encoding, Nox-organizing protein 1 (NOXO1), a novel p47phox homolog required for Nox1 activity. In addition, H. pylori LPS activated Rac1; i.e., it converted Rac1 to the GTP-bound state. A phosphoinositide 3-kinase inhibitor, LY-294002, blocked H. pylori LPS-induced Rac1 activation and O2- generation without interfering with the expression of Nox1 and NOXO1 mRNA. O2- production inhibited by LY-294002 was completely restored by transfection of an adenoviral vector encoding a constitutively active Rac1 but not an inactive Rac1 or a constitutively active Cdc42. These findings indicate that Rac1 plays a crucial role in Nox1 activation. Thus the H. pylori LPS-stimulated O2- production in gastric mucosal cells appears to require two distinct events: 1) transcriptional upregulation of Nox1 and NOXO1 and 2) activation of Rac1.
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PMID:Helicobacter pylori lipopolysaccharide activates Rac1 and transcription of NADPH oxidase Nox1 and its organizer NOXO1 in guinea pig gastric mucosal cells. 1546 54

The SHIP1 (SH2-containing inositol-5'-phosphatase 1) acts as a negative regulator of proliferation, survival and end cell activation in haemopoietic cells. It does so, at least in part, by translocating to membranes after extracellular stimulation and hydrolysing the phosphoinositide 3-kinase-generated second messenger, PtdIns(3,4,5)P(3) to PtdIns(3,4)P(2). SHIP1(-/-) mice have, as a result, an increased number of neutrophils and monocyte/macrophages because their progenitors display enhanced survival and proliferation. These mice also suffer from osteoporosis because of an increased number of hyperactive osteoclasts and a significant neutrophil infiltration of the lungs. Interestingly, SHIP1(-/-) mice do not display endotoxin tolerance and we have found that lipopolysaccharide-induced endotoxin tolerance is contingent on up-regulating SHIP1, through the production of autocrine-acting transforming growth factor-beta, in bone-marrow-derived macrophages and mast cells. Intriguingly, unlike bone-marrow-derived macrophages, SHIP1(-/-) peritoneal and alveolar macrophages produce 10-fold less NO than wild-type macrophages because these in vivo-generated macrophages have very high arginase I levels and this enzyme competes with inducible nitric oxide synthase for the substrate L-arginine. It is probable that, in the face of chronically increased PtdIns(3,4,5)P(3) levels in their myeloid progenitors, SHIP1(-/-) mice display a skewed development away from M1 (killer) macrophages (which have high inducible nitric oxide synthase levels and produce NO to kill microorganisms and tumour cells), towards M2 (healing) macrophages (which have high arginase levels and produce ornithine to promote host-cell growth and collagen formation). This skewing probably occurs to avoid septic shock and suggests that the phosphoinositide 3-kinase pathway plays a critical role in programming macrophages.
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PMID:The role of SHIP1 in macrophage programming and activation. 1549 15

PI3K (phosphoinositide 3-kinase) I(A) family members contain a regulatory subunit and a catalytic subunit. The p110delta catalytic subunit is expressed predominantly in haematopoietic cells. There, among other functions, it regulates antigen receptor-mediated responses. Using mice deficient in the p110delta subunit of PI3K, we investigated the role of this subunit in LPS (lipopolysaccharide)-induced B cell responses, which are mediated by Toll-like receptor 4 and RP105. After injection of DNP-LPS (where DNP stands for 2,4-dinitrophenol), p110delta(-/-) mice produced reduced levels of DNP-specific IgM and IgG when compared with wild-type mice. In vitro, the proliferation and up-regulation of surface activation markers such as CD86 and CD25 induced by LPS and an antibody against RP105 were decreased. We analysed the activation state of key components of the LPS pathway in B cells to determine whether there was a defect in signalling in p110delta(-/-) B cells. They showed normal extracellular-signal-regulated kinase phosphorylation, but anti-RP105-induced protein kinase B, IkappaB (inhibitor of nuclear factor kappaB) and c-Jun N-terminal kinase activation was severely reduced. This demonstrates that the p110delta subunit of PI3K is involved in the LPS response in B cells and may represent a link between the innate and the adaptive immune system.
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PMID:The p110delta subunit of phosphoinositide 3-kinase is required for the lipopolysaccharide response of mouse B cells. 1549 16

The expression of inducible nitric-oxide synthase (iNOS) and subsequent "high-output" nitric oxide (NO) production underlies the systemic hypotension, inadequate tissue perfusion, and organ failure associated with septic shock. Therefore, modulators of iNOS expression and activity, both endogenous and exogenous, are important in determining the magnitude and time course of this condition. We have shown previously that NO from the constitutive endothelial NOS (eNOS) is necessary to obtain maximal iNOS expression and activity following exposure of murine macrophages to lipopolysaccharide (LPS). Thus, eNOS represents an important regulator of iNOS expression in vitro. Herein, we validate this hypothesis in vivo using a murine model of sepsis. A temporal reduction in iNOS expression and activity was observed in LPS-treated eNOS knock-out (KO) mice as compared with wild-type animals; this was reflected in a more stable hemodynamic profile in eNOS KO mice during endotoxaemia. Furthermore, in human umbilical vein endothelial cells, LPS leads to the activation of eNOS through phosphoinositide 3-kinase- and Akt/protein kinase B-dependent enzyme phosphorylation. These data indicate that the pathogenesis of sepsis is characterized by an initial eNOS activation, with the resultant NO acting as a co-stimulus for the expression of iNOS, and therefore highlight a novel pro-inflammatory role for eNOS.
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PMID:Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived no in vivo. 1564 65


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