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)

Renal tubular epithelial cells are largely resistant to oxidant-induced injury despite their capacity to accumulate relatively high concentrations of potentially damaging prooxidant and thiol-depleting agents. In the present study, we tested the hypothesis that such resistance may be attributable to a lack or deficiency of signaling transduction pathways through which reactive oxidants have been shown to promote the activation of NF-kappaB, a transcriptional factor that is known to mediate the inducible expression of a wide variety of genes that are involved in inflammatory and other cytotoxic reactions in numerous cell types. NF-kappaB was found to be readily activated following exposure of cultured normal rat kidney epithelial (NRK52E) cells to bacterial lipopolysaccharide (LPS). However, in contrast to findings with many other cell types, the activation of NF-kappaB by LPS was not substantially altered either by pretreatment of cells with the thiol antioxidant, N-acetylcysteine, or by glutathione (GSH) depletion. Moreover, reactive oxidants and oxidative stress-generating chemicals were completely without effect with respect to NF-kappaB activation in NRK52E cells, even following GSH depletion. In contrast, LPS activation of NF-kappaB was substantially attenuated by the intracellular Ca2+ chelator, Quin 2AM, and by the Ca-channel inhibitor, ruthenium red. Moreover, thapsigargin, a Ca-ATPase inhibitor, promoted NF-kappaB activation comparable to that observed by LPS. Additionally, staurosporine, a Ca-dependent protein kinase C inhibitor, substantially decreased LPS-mediated NF-kappaB activation. These results demonstrate that the LPS-inducible expression of NF-kappaB in renal epithelial cells, in contrast to many other cell types, is not responsive to oxidative stress and is regulated, at least in part, by redox-insensitive modulation of intracellular calcium levels. These findings provide a basis for the highly tissue-specific expression and function of NF-kappaB in kidney epithelial cells, which may underlie their resistance to oxidant-mediated cytotoxicity.
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PMID:Activation of NF-kappaB in normal rat kidney epithelial (NRK52E) cells is mediated via a redox-insensitive, calcium-dependent pathway. 993 Dec 81

Using radioimmunoassay, we studied the endothelin (ET) production of alveolar macrophages(AM) of the rats. The results showed that: (1) a basal amount of ET which was time-dependent (r = 0.7415, P < 0.01) was detected in supernatant of cultured unstimulated AM; (2) lipopolysaccharide (LPS), PMA, or A23187 could increase the ET production of AM (P < 0.01) (3) calmodulin antagonist W7 reduced the ET production of LPS or A23187-stimulated AM (P < 0.05, P < 0.01), but did not effect that of PMA-stimulated AM; protein kinase C inhibitor H7 attenuated the effect of PMA on ET production (P < 0.01), but did not effect LPS on ET production; (4) prostaglandin E2 (PGE2) inhibited the ET production of LPS-stimulated (P < 0.05) and PMA-stimulated AM (P < 0.05); cyclooxygenase inhibitor indomethacin enhanced the effect of LPS on ET production (P < 0.01), but did not effect PMA on ET production. We conclude that AM is an important source of ET in the lungs both at physiologic and pathologic situation there are two pathways of signal transduction for factors stimulating ET production of AM, i.e., PKC-dependent and Ca(2+)-calmodulin-dependent pathways; the autocrine PGEs from AM shows a negatively modulated effect on ET production of AM.
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PMID:[Modulated effects of prostaglandin E2 on endothelin production of alveolar macrophages in rats]. 1068 42

Macrophages form a crucial bridge between the innate and adaptive immune response. One of their most important functions is to recognize infectious microorganisms. Toll-like receptors (TLRs) are key elements in pathogen recognition, and among them, TLR2 and TLR4 are most discussed. However, expression patterns of TLRs during myeloid cell differentiation to macrophage are unknown. In this study, we examined differentiation in the model human myeloid cell line, HL-60, treated with phorbol 12-myristate 13-acetate (PMA) or VitD(3). Expression of TLR2, TLR4, and CD14 were measured by reverse transcription-PCR, RNase protection assay, and fluorescence-activated cell sorter assays. After treatment by PMA (1, 10, and 100 nM) for 12, 24, and 48 h, expression of TLR2 and CD14 mRNA was increased in a time- and dose-dependent manner. However, VitD(3) only induced expression of CD14 but not TLR2 in HL-60 cells. TLR4 was expressed constitutively before differentiation and increased slightly after that. Thus, PMA-mediated differentiation of HL-60 cells to macrophages is associated largely with TLR2 expression and, to a much lesser extent, with TLR4. Furthermore, up-regulation of TLR2 and CD14 mRNA expression by PMA was abrogated by a protein kinase C inhibitor, Calphostine C, suggesting the up-regulation of TLR2 and CD14 mRNA is dependent on the activation of protein kinase C. Coexpression of CD14/TLR2 and/or CD14/TLR4 may be essential but not sufficient for the production of tumor necrosis factor-alpha in response to lipopolysaccharide in our system.
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PMID:Expression of toll-like receptors 2 and 4 and CD14 during differentiation of HL-60 cells induced by phorbol 12-myristate 13-acetate and 1 alpha, 25-dihydroxy-vitamin D(3). 1180 29

Toll-like receptors (TLRs) have been previously shown to mediate oxidative burst in chicken heterophils. This study was conducted to begin to map the molecular pathways that regulate TLR-mediated oxidative burst. Peripheral blood heterophils from neonatal chicks were isolated and exposed to known inhibitors of signal transduction pathways for either 20 min (genistein, verapamil, or chelerythrine) or 120 min (pertussis toxin) at 39 degrees C. The cells were then stimulated for 30 min at 39 degrees C with Salmonella enteritidis lipopolysaccharide (LPS) or Staphylococcus aureus lipoteichoic acid (LTA). The heterophil oxidative burst was then quantitated by luminol-dependent chemiluminescence (LDCL). Genistein (a tyrosine kinase inhibitor), verapamil (a calcium channel blocker), chelerythrine (a protein kinase C inhibitor), and pertussis toxin (a G-protein inhibitor) significantly reduced LPS-stimulated oxidative burst in chicken heterophils by 34, 50, 63, and 51%, respectively. Although genistein had a statistically significant effect on reducing LPS-stimulated LDCL biologically it seems to play only a minor role within the oxidative burst pathway. Heterophils stimulated with the gram-positive TLR agonist, LTA, activated a different signal transduction pathway since chelerythrine was the only inhibitor that significantly reduced (72%) LTA-stimulated oxidative burst. These findings demonstrate that distinct signal transduction pathways differentially regulate the stimulation of oxidative burst in avian heterophils. Pertussis toxin-sensitive, protein kinase C-dependent, Ca(++)-dependent G proteins appear to regulate oxidative burst of avian heterophils stimulated with gram-negative agonist LPS; whereas, a protein kinase C-dependent signal transduction pathway plays the major role activating the oxidative burst of avian heterophils stimulated with gram-positive agonists. The distinct differences in the response of heterophils to these two agonists illustrate the specificity of TLRs to pathogen-associated molecular patterns (PAMP)s.
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PMID:Differential activation of signal transduction pathways mediating oxidative burst by chicken heterophils in response to stimulation with lipopolysaccharide and lipoteichoic acid. 1452 75

The recruitment of monocytes appears to be a crucial factor for inflammatory lung disease. Alveolar epithelial cells contribute to monocyte influx into the lung, but their impact on monocyte inflammatory capacity is not entirely clear. We thus analyzed the modulation of monocyte oxidative burst by A549 and isolated human alveolar epithelial cells. Epithelial infection with Moraxella catarrhalis induced monocyte adhesion, transepithelial migration, and superoxide generation, whereas stimulation with lipopolysaccharide, tumor necrosis factor-alpha, interleukin-1beta, or interferon-gamma induced adhesion or transmigration, but failed to initiate monocyte burst. The effect of microbial challenge was mimicked by phorbol myristate acetate and inhibited by the protein kinase C inhibitor bisindoylmaleimide. Furthermore, evidence for a role of platelet-activating factor-signaling in monocytes is presented. Monocyte burst was neither induced by supernatant nor affected by fixation of A549 cells, excluding the contribution of epithelium-derived soluble factors but emphasizing the mandatory role of intercellular contact. The employment of blocking antibodies, however, denied a role for the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, or CD11b/CD18 and CD49d/CD29. In essence, infection of alveolar epithelial cells with M. catarrhalis might amplify the inflammatory capacity of invading monocytes eliciting their superoxide production. The epithelial response to this microbial challenge thus clearly differed from that to proinflammatory cytokines.
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PMID:Moraxella catarrhalis--infected alveolar epithelium induced monocyte recruitment and oxidative burst. 1555 18

Efficient clearance of apoptotic cells is essential for tissue homeostasis, allowing for cellular turnover without inflammatory consequences. The Mer (Nyk and c-Eyk) receptor tyrosine kinase (Mertk) is involved in two aspects of apoptotic cell clearance by acting as a receptor for Gas6, a gamma-carboxylated phosphatidylserine-binding protein that bridges apoptotic and viable cells. First, Mertk acts in a bona fide engulfment pathway in concert with alphavbeta5 integrin by regulating cytoskeletal assemblages, and second, it acts as a negative regulator for inflammation by down-modulating pro-inflammatory signals mediated from bacterial lipopolysaccharide-Toll-like receptor 4 (TLR4) signaling, and hence recapitulating anti-inflammatory immune modulation by apoptotic cells. Here we describe Mertk post-receptor events that govern phagocytosis and cytoskeletal signaling are principally mediated by autophosphorylation site Tyr-867. Using the Mertk Y867F mutant and pharmacological inhibitors, we show that Tyr-867 is required for phosphatidylinositol 3-kinase and phospholipase Cgamma2 activation; their activation in turn elicits protein kinase C-dependent signals that act on the actin cytoskeleton. Although Mertk(Y867F) blocked the tyrosine phosphorylation of FAK on Tyr-861 and p130(cas) and also abrogated the phagocytosis of apoptotic cells, this mutant did not suppress lipopolysaccharide-inducible NF-kappaB transcription, nor was NF-kappaB activation dependent on the protein kinase C inhibitor, calphostin C. Finally, unlike the cytoskeletal events associated with Tyr-867 autophosphorylation, the trans-inhibition of NF-kappaB occurred in a postnuclear-dependent fashion independent of cytosolic IkappaB phosphorylation and p65/RelA sequestration. Taken together, these data suggest that Mertk has distinct and separable effects for phagocytosis and for resolving inflammation, providing a molecular rationale for how immune licensing and inflammation can be dissociated from phagocytosis in a single phagocytic receptor.
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PMID:Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine kinase allows for dissociation of multiple signaling pathways for phagocytosis of apoptotic cells and down-modulation of lipopolysaccharide-inducible NF-kappaB transcriptional activation. 1803 60

Activation and injury of microglial cells are involved in a broad range of brain diseases including stroke, brain infection and neurodegenerative diseases. However, there is very little information regarding how to reduce microglial reaction and preserve these cells to provide neuroprotection. Here, we showed that the incubation of C8-B4 mouse microglial cells with lipopolysaccharide (LPS) plus interferon-gamma (IFNgamma) for 24 h decreased the viability of these cells. Pretreatment of these cells with 1%, 2% or 3% isoflurane, a commonly used volatile anesthetic, for 1 h at 30 min before the exposure to LPS plus IFNgamma attenuated the reduction of cell viability (preconditioning effect). LPS plus IFNgamma also activated these microglial cells to express inducible nitric oxide synthase (iNOS) and to induce accumulation of nitrite, a stable oxidation product of nitric oxide, in the incubation medium. Isoflurane preconditioning attenuated these LPS plus IFNgamma effects on the iNOS expression and nitrite accumulation. Aminoguanidine, an iNOS inhibitor, attenuated the LPS plus IFNgamma-induced glutamate release and decrease of microglial viability. Isoflurane preconditioning also reduced LPS plus IFNgamma-induced glutamate release. Exogenous glutamate decreased microglial viability. Finally, the isoflurane preconditioning-induced protection was abolished by chelerythrine, a protein kinase C inhibitor. These results suggest that LPS plus IFNgamma activates the iNOS-nitric oxide-glutamate pathway to induce microglial injury and that this activation is attenuated by isoflurane preconditioning. Protein kinase C may be involved in the isoflurane preconditioning effects.
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PMID:Isoflurane preconditioning reduces mouse microglial activation and injury induced by lipopolysaccharide and interferon-gamma. 1849 58

Tumor-associated macrophages are immune cells with diverse functions in tumor development. Among other functions, they downregulate immune-mediated tumor rejection by depriving lymphocytes of nutrients. The essential amino acid tryptophan is metabolized by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase (TDO). Indoleamine 2,3-dioxygenase 1 is expressed in a large number of human tumors, and inhibitors are in development to improve immunotherapy. Tryptophan 2,3-dioxygenase was also found in human tumors and preclinical working models confirmed its immunosuppressive power. We explored a potential expression of TDO by macrophages. This enzyme could be induced in two human cell lines, THP-1 and U937, by incubation with phorbol myristate acetate, lipopolysaccharide, and interferon gamma. Phorbol-myristate-acetate-mediated induction was inhibited by rottlerin, a protein kinase C inhibitor. In contrast to these monocytic cell lines, other cell lines or fresh human monocytes isolated from peripheral blood mononuclear cells and differentiated into proinflammatory or anti-inflammatory macrophages could not be induced to express TDO. Our results suggest that TDO might play an immunosuppressive role in human monocytic leukemias but not in untransformed macrophages.
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PMID:Induction of tryptophan 2,3-dioxygenase expression in human monocytic leukemia/lymphoma cell lines THP-1 and U937. 3190 23


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