Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently shown that endothelial cell-derived IL-8 inhibits neutrophil adhesion to IL1-beta-activated human umbilical vein endothelial cell monolayers. IL-8 secreted by T lymphocytes or monocytes has been characterized as a promoter of neutrophil degranulation and chemotaxis. The IL-8 isolated from each of these cell types is a mixture of two IL-8 polypeptides, one consisting of 72 amino acids (herein called [ser-IL-8]72) and the other 77 amino acids (an N-terminal extended form herein called [ala-IL-8]77). IL-8 derived from T lymphocytes and monocytes is predominantly [ser-IL-8]72, whereas endothelial-derived IL-8 is highly enriched (greater than 80%) in [ala-IL-8]77. We address the relationship and activities of these two forms of IL-8 using recombinant proteins expressed by both mammalian cells and Escherichia coli. Thrombin was found to efficiently convert [ala-IL-8]77 to [ser-IL-8]72. In contrast, urokinase and tissue-type plasminogen activator were unable to cleave [ala-IL-8]77, and trypsin generated multiple IL-8 cleavage fragments. In competitive binding assays using 125I[ala-IL-8]77 neutrophils exhibited a twofold preference for [ser-IL-8]72 over [ala-IL-8]77. Both forms of IL-8 inhibited neutrophil adhesion to IL-1-beta-activated HUVEC monolayers by up to 90%. However, [ser-IL-8]72 was approximately 10-fold more potent than [ala-IL-8]77 in these assays (ED50 approximately 0.3 nM for [ser-IL-8]72 vs approximately 3 nM for [ala-IL-8]77. Both forms of IL-8 promoted degranulation of cytochalasin B-treated neutrophils [[ser-IL-8]72 (ED50 greater than 10 nM) was two- to three-fold more potent than [ala-IL-8]77], although in this regard they were less active than FMLP. Our data suggest that [ala-IL-8]77 and [ser-IL-8]72 have qualitatively similar and potentially complex biological activities, and that full activation of IL-8 requires cleavage to the [ser-IL-8]72 form. In the case of inflamed endothelial cells this activation could be mediated by thrombin generated in the procoagulant environment associated with these cells.
 ...
PMID:Endothelial and leukocyte forms of IL-8. Conversion by thrombin and interactions with neutrophils. 221 72

Stimulated human monocytes release several proteins thought to play a role in inflammation, including interleukin 1, tumor necrosis factor, and plasminogen activator. We have purified another proinflammatory protein that is chemotactic for human neutrophils from conditioned medium of lipopolysaccharide-stimulated monocytes. After a series of steps that included anion-exchange chromatography, gel filtration, and HPLC on cation-exchange and reverse-phase columns, an apparently pure protein was obtained that migrated as a single 7-kDa band on NaDodSO4/polyacrylamide gels under reducing or nonreducing conditions. The amino acid composition of this monocyte-derived neutrophil chemotactic factor was different from that of interleukin 1 and tumor necrosis factor. N-terminal amino acid sequence of the first 42 residues was determined. This portion of the molecule has up to 56% sequence similarity with several proteins that may be involved in host responses to infection or tissue injury. It is identical to a portion of a sequence deduced from an mRNA induced by staphylococcal enterotoxin treatment of human leukocytes. At the optimal concentration of 10 nM, 50% of neutrophils added to chemotaxis assay wells migrated toward the pure attractant. Potency and efficacy are comparable to that of fMet-Leu-Phe, which is often used as a reference. In contrast to many attractants, the protein was not chemotactic for human monocytes.
 ...
PMID:Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. 348 May 40

We measured serum levels of endotoxin, cytokines, and eicosanoids and investigated their relationship to serum complement levels in patients with sepsis. Serum endotoxin (Et) levels (5.3 +/- 2.4 pg/ml) were within the normal range, but levels of tumor necrosis factor-alpha (TNF-alpha, 114 +/- 104.94 pg/ml), interleukin 6 (IL-6, 86.7 +/- 50.9 pg/ml), interleukin 8 (IL-8, 86.8 +/- 49.7 pg/ml), type-II phospholipase A2 (type II PLA2, 211.3 +/- 193.9 ng/ml), leukotriene B4 (LTB4, 88.7 +/- 27.2 pg/ml), thromboxane B2 (TXB2, 58.7 +/- 50.9 pg/ml) and 6-keto-prostaglandin F1 alpha (PGF1 alpha, 21.0 +/- 11.0 pg/ml) levels were above normal. Levels of C3a (1088.4 +/- 83.8.7 ng/ml) and C4a (1951.5 +/- 1697.8 ng/ml) were also above normal; C3 (66.0 +/- 25.6 mg/dl) and C4 (23.6 +/- 5.3 mg/dl) were within the normal range, and C5a was lower than the detectable limit in all but one of the subjects. Serum TNF-alpha was significantly correlated with C3a (p < 0.001). Serum IL-6 had a significant negative correlation with C3 (p = 0.002) and C4 (p = 0.010). Type II PLA2 was significantly correlated with C3a (p < 0.001). There were no significant correlations between serum Et or IL-8 and serum C3, C4, C3a or C4a. Our findings suggest that increased levels of TNF-alpha, IL-6, and Type II PLA/ in patients with sepsis contribute to activation of the complement system.
 ...
PMID:Blood cytokine and complement levels in patients with sepsis. 793 3

IL-10 protects mice from LPS-induced lethality. To determine the effects of IL-10 on LPS-induced inflammatory responses, six Papio anubis baboons were i.v. injected with a sublethal dose of LPS (Salmonella typhimurium; 500 microg/kg) directly preceded by either human rIL-10 (n = 3, 500 microg/kg) or diluent (n = 3). IL-10 strongly inhibited LPS-induced release of TNF, IL-6, IL-8, and IL-12 (all p < 0.05). By contrast, IL-10 did neither influence the activation of the coagulation system (plasma levels of thrombin/antithrombin III complexes), nor the activation of the fibrinolytic system (plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor type I, and plasmin/alpha 2-antiplasmin complexes). IL-10 modestly attenuated neutrophilic leukocytosis and neutrophil degranulation (plasma concentrations of elastase/alpha1-antitrypsin complexes) (both p < 0.05). Changes in surface TNF receptor expression on circulating granulocytes were not affected by IL-10. These results suggest that during sublethal endotoxemia the predominant anti-inflammatory effect of IL-10 treatment is inhibition of proinflammatory cytokine release.
 ...
PMID:Effects of IL-10 on systemic inflammatory responses during sublethal primate endotoxemia. 902 40

Inflammatory response in tissue results from a complex network of interactions between inflammatory cells (mast cells, eosinophils, basophils, macrophages) and resident cells belonging to the lung structure (like endothelial cells, fibroblasts, epithelial cells). Among structural cells, endothelial cells play a critical role. The important role of endothelium is also reflected in the fact that it occupies an area exceeding 1000 m2. Thus, endothelium is the largest and the most active paracrine organ in the body, producing potent vasoactive, procoagulant, anticoagulant, and proinflammatory substances. Endothelial cells have four key functions that alter in the process of inflammation: 1 a) Regulation and control of leukocyte traffic through the expression of adhesion molecules (selectins E and P, molecules of immunoglobulin superfamily ICAM-1, ICAM-2, VCAM); 1 b) They are also able to amplify leukocyte activation through the production of proinflammatory cytokines like IL-1, IL-6 and chemokines like IL-8 and RANTES molecules; 2) Regulation of vascular tone by production of PGI-2, EDRF/NO and elements of local renin-angiotensin system; 3) Regulation of local coagulation by controlling the production of t-PA and PAI-1; 4) Regulation of the vascular permeability. In the states of acute inflammation, the endothelial cell takes on a proinflammatory phenotype and as such becomes chemoattractant, facilitating leukocyte adhesion, activation and migration, becomes prothrombotic and demonstrates enhanced vascular permeability.
 ...
PMID:[The role of endothelial cells in allergic inflammation reactions]. 986 70

To determine in vivo effects of interleukin (IL)-12 on host inflammatory mediator systems, 4 healthy chimpanzees received recombinant human IL-12 (1 microg/kg) by intravenous injection. IL-12 induced increases in plasma concentrations of IL-15, IL-18, and interferon-gamma (IFN-gamma), plus a marked antiinflammatory cytokine response (IL-10, soluble tumor necrosis factor [TNF] receptors, IL-1 receptor antagonist) and secretion of alpha-chemokines (IL-8, IFN-gamma-inducible protein 10) and beta-chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta). In addition, IL-12 elicited neutrophilic leukocytosis, neutrophil degranulation (elastase-alpha1-antitrypsin complexes), coagulation activation (F1 + 2 prothrombin fragment, thrombin-antithrombin III complexes), and fibrinolytic activation (tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes). IL-12-induced activation of multiple host mediator systems was found only after 8-24 h, remained detectable until the end of the 48-h observation period, and occurred in the absence of detectable TNF and IL-1beta. These data may contribute to understanding the role of IL-12 in the pathogenesis of sepsis syndrome and the toxicity found after repeated injections of IL-12.
 ...
PMID:Interleukin-12 induces sustained activation of multiple host inflammatory mediator systems in chimpanzees. 995 71

We have proposed that exposure of epithelial cell membrane lipids in the lung (mainly phospholipids) to ozone will generate lipid ozonation products (LOP), which could be responsible for the proinflammatory effects of ozone. The ozonation of phosphocholine, the principal membrane phospholipid, produces a limited number of LOP, including hydroxyhydroperoxides and aldehydes. We now report that exposure of cultured human bronchial epithelial cells to the ozonized 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) product, 1-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine (PC-ALD), a phospholipase A(2) (PLA(2))-stimulatory LOP, resulted in a 113 +/- 11% increase in the amounts of tritiated platelet-activating factor ((3)H-PAF) released apically. (3)H-PAF release was also induced by 1-hydroxy-1-hydroperoxynonane of ozonized POPC (HHP-C9), a phospholipase C (PLC)- stimulatory LOP (134 +/- 40% increase in (3)H-PAF). PC-ALD at 10 microM, but not HHP-C9, induced a 127 +/- 24% increase in prostaglandin E(2) (PGE(2)) release (n = 6, p < 0.05). In contrast, HHP-C9, but not PC-ALD, induced interleukin (IL)-6 release (178 +/- 23% increase, n = 6, p < 0.05) and IL-8 release (101 +/- 23% increase, n = 8, p < 0. 05). These results suggest that LOP-dependent release of proinflammatory mediators may play an important role in the early inflammatory response seen during exposure to ozone.
 ...
PMID:Induction of inflammatory mediators in human airway epithelial cells by lipid ozonation products. 1058 9

Gene therapy utilizing leukocytes is an unexplored therapeutic strategy for targeting tissue-type plasminogen activator (t-PA) to fibrin and sites of inflammation. In this study, five cationic lipids were observed to enhance the adenovirus (Ad)-mediated expression of t-PA in human peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner between 1000 and 15,000 lipid molecules per Ad particle (efficiency:LipofectAMINE > GenePORTER > Effectene > SuperFect > DMRIE-C). PBMCs treated with Ad/t-PA * LipofectAMINE complexes displayed elevated t-PA expression over a 4-day period and the t-PA-expressing cells facilitated the lysis of plasma clots in vitro. Functional and immunologic assays revealed that the Ad * LipofectAMINE infection protocol did not affect monocyte adhesion in vitro or elevate the expression of procoagulant activity, interleukin 8, or tumor necrosis factor alpha. The potential of this system was documented with an in vivo rat model system that involved the injection of lipopolysaccharide into the peritoneal cavity to induce an inflammatory response. Infusion of Ad/t-PA-infected rat PBMCs into the vasculature of lipopolysaccharide-treated animals was found to increase local fibrinolytic activity by 4-fold. These data provide a framework for utilizing adenovirus to transfer genes into PBMCs.
 ...
PMID:Modulating the fibrinolytic system of peripheral blood mononuclear cells with adenovirus. 1124 35

1. In acute respiratory distress syndrome (ARDS) induced by endotoxins, a high production of inflammatory mediators by microvascular lung endothelial cells (LMVEC) can be observed. Activation of cells by endotoxins may result in elevated secretion of phospholipase A(2) (sPLA(2)) which is thought to contribute to tissue damage. The present study was undertaken to investigate the role of sPLA(2) in chemokine production in human lung microvascular endothelial cells (LMVEC) stimulated with the endotoxins lipopolysaccharide (LPS) and lipoteichoic acid (LTA). In particular, we investigated the effects of sPLA(2) inhibitors, specifically, the extracellular PLA(2) inhibitors (ExPLIs), composed of N-derivatized phosphatidyl-ethanolamine linked to polymeric carriers, and LY311727, a specific inhibitor of non-pancreatic sPLA(2). 2. ExPLIs markedly inhibited LPS and LTA induced production and mRNA expression of the neutrophile attracting chemokines IL-8, Gro-alpha and ENA-78, as well as of the adhesion molecules ICAM-1 and E-selectin. Concomitantly, ExPLIs inhibited the LPS-induced activation of NF-kappaB by LPS but not its activation by TNF-alpha or IL-1. 3. Endotoxin mediated chemokine production in LMVEC seems not to involve PLA(2) activity, since LPS stimulation was not associated with activation of intracellular or secreted PLA(2). It therefore seems that the inhibitory effect of the ExPLIs was not due to their PLA(2) inhibiting capacity. This was supported by the finding that the LPS-induced chemokine production was not affected by the selective sPLA(2) inhibitor LY311727. 4. It is proposed that the ExPLIs may be considered a prototype of potent suppressors of specific endotoxin-induced inflammatory responses, with potential implications for the therapy of subsequent severe inflammation.
 ...
PMID:Inhibition of LPS-induced chemokine production in human lung endothelial cells by lipid conjugates anchored to the membrane. 1193 6

The endothelium is the primary barrier to leukocyte recruitment at sites of inflammation. Neutrophil recruitment is directed by transendothelial gradients of IL-8 that, in vivo, are bound to the endothelial cell surface. We have investigated the identity and function of the binding site(s) in an in vitro model of neutrophil transendothelial migration. In endothelial culture supernatants, IL-8 was detected in a trimolecular complex with heparan sulfate and syndecan-1. Constitutive shedding of IL-8 in this form was increased in the presence of a neutralizing Ab to plasminogen activator inhibitor-1 (PAI-1), indicating a role for endothelial plasminogen activator in the shedding of IL-8. Increased shedding of IL-8/heparan sulfate/syndecan-1 complexes was accompanied by inhibition of neutrophil transendothelial migration, and aprotinin, a potent plasmin inhibitor, reversed this inhibition. Platelets, added as an exogenous source of PAI-1, had no effect on shedding of the complexes or neutrophil migration. Our results indicate that IL-8 is immobilized on the endothelial cell surface through binding to syndecan-1 ectodomains, and that plasmin, generated by endothelial plasminogen activator, induces the shedding of this form of IL-8. PAI-1 appears to stabilize the chemoattractant form of IL-8 at the cell surface and may represent a therapeutic target for novel anti-inflammatory strategies.
 ...
PMID:Plasminogen activator inhibitor-1 supports IL-8-mediated neutrophil transendothelial migration by inhibition of the constitutive shedding of endothelial IL-8/heparan sulfate/syndecan-1 complexes. 1290 11


1 2 3 4 Next >>