Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prophylactic vaccinations may sometimes shorten the incubation period of some illnesses and/or convert a latent infection/inflammation into a clinically apparent disease. Cytokines play a major role in mediating the inflammatory process in various clinical entities and represent a potential source of tissue damage if their production is not sufficiently well controlled. It seems that irregularities in production of proinflammatory cytokines may be responsible for the abnormalities associated with full-blown clinical symptoms of various urinary tract diseases observed after DTP vaccination in 13 infants and young children hospitalized over the past 24 years. On admission, upper respiratory tract diseases, atopic dermatitis, and/or latent urinary tract infection/inflammation were found in these children. It is suggested that the whole-cell pertussis present in DTP vaccine, acting as an excessive stimulus in these patients, produced symptoms reminiscent of biologic responses to circulating proinflammatory monokines such as IL-1beta, TNF-alpha, and IL-6 because earlier it was reported that in vitro the whole-cell vaccine induced significantly more such cytokine production than did the acellular pertussis or diphtheria-tetanus-only vaccine. Analysis of the cellular immune disturbances previously reported in urinary tract infection/inflammation (increased serum and/or urinary IL-1alpha, IL-1 receptor antagonist, IL-6 and IL-8), steroid-sensitive nephrotic syndrome (increased IL-2, IFN-gamma, TNF-alpha, and decreased or increased IL-4, depending on the cells studied), and atopic dermatitis (decreased IFN-gamma and increased IL-4 production), may suggest that similar subclinical chronic cytokine-mediated abnormalities produced in the course of latent diseases revealed in our patients, combined with those caused by DTP vaccination stimulus, were responsible for the pathomechanism of these clinical entities. This speculation is in agreement with the reports on the long-lasting induction of cytokine release and down-regulation of hepatic cytochrome P-450 isoenzyme activities after administration of DTP vaccine to mice and may be supported by the fact that TH1 phenotype is associated with the up-regulation of intercellular adhesion molecule-1 and RANTES, whereas TH2 phenotype is associated with the up-regulation of the vascular cell adhesion molecule and P-selectin, which are key players in the migration into inflamed tissues and localization of lymphocytes and other allergic effector and inflammatory cells. Because several inflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting the metabolism of several endogenous lipophilic substances such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances, their irregularities in the body may eventually lead to the flare of latent diseases in some predisposed subjects. Also, interleukin genetic polymorphisms, especially the constellation of TNF-alpha and IL-6 genetic variants, might predispose some infants with infection to a more than usually intense inflammatory response in the kidneys after vaccination. It seems that the aforementioned pathomechanism may also be responsible for some cases of sudden infant death syndrome, which is often preceded by infection/inflammation.
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PMID:Urinary tract diseases revealed after DTP vaccination in infants and young children: cytokine irregularities and down-regulation of cytochrome P-450 enzymes induced by the vaccine may uncover latent diseases in genetically predisposed subjects. 1535 30

Inflammatory processes play a crucial role in the pathogenesis of atherosclerosis and other vascular disorders. We hypothesized that ischemia of the ductus arteriosus might initiate an active inflammatory response that could play a role in ductus remodeling and permanent closure. To test this hypothesis, we studied effects of postnatal ductus construction on inflammatory processes and remodeling in late-gestation fetal and newborn baboons, and preterm newborn baboons. After postnatal ductus constriction, the expression of several genes known to be essential for atherosclerotic remodeling [vascular cell adhesion molecule (VCAM)-1, E-selectin, IL-8, macrophage colony stimulating factor-1, CD154, interferon-gamma, IL-6, and tumor necrosis factor-alpha] was increased in the ductus wall. We were unable to detect intercellular adhesion molecule (ICAM)-1, ICAM-2, P-selectin, monocyte chemoattractant protein-1, or IL-1 by either real-time PCR or immunohistochemistry. VCAM-1, which is newly expressed by luminal cells of the closed ductus, is an important ligand for the mononuclear cell adhesion receptor VLA4. After postnatal constriction, VLA4+ monocytes/macrophages (CD68+ and CD14+) and, to a lesser extent, T-lymphocytes adhered to the ductus wall. Neutrophils and platelets were not observed. The extent of postnatal neointimal remodeling (both endothelial cell layering and subendothelial space thickening) was associated with the degree of mononuclear cell adhesion. Similarly, the extent of vasa vasorum ingrowth correlated with the invasion of CD68+ cells, from the adventitia into the muscle media. Based on these data, we conclude that the inflammatory response following postnatal ductus constriction may be as necessary for ductus remodeling as it is for atherosclerotic remodeling.
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PMID:The role of monocyte-derived cells and inflammation in baboon ductus arteriosus remodeling. 1561 59

The placental-umbilical unit in sickle cell disease (SCD) pregnancy was used to explore hypoxia in vivo, an important factor in the pathophysiology of this disease. Gross examination and microscopic analysis of the placentas, taken immediately after delivery, indicate good concordance between maturity and term as controls, but higher frequency of vascular injuries such as excess syncytial knots, excess fibrin deposits, congestion and villous necroses. Unexpectedly, neither leukocyte recruitment nor alteration in extraplacental membrane was observed, suggesting the absence of inflammation. Additionally, interleukin (IL)-6 and IL-8 concentrations, measured by enzyme-linked immunosorbent assay (ELISA), were similar in the placental maternal blood from controls and SCD. There were also no significant differences found in IL-6 vein blood concentrations between controls and SCD, IL-8 being not detected. Immunostaining of umbilical vein endothelium in SCD pregnancies showed redistribution of PECAM-1 (CD31), von Willebrand factor (vWF), and P-selectin to the cell surface, controls exhibiting the classical pattern. Staining quantification indicated increases in vWF (+36.2%; P=.006) and vascular endothelial growth factor (VEGF) expression (+96.0%; P=.006) over control, but a reduction in endothelial nitric oxide synthase (eNOS) (-45.5%; P=.029). These results document, for the first time, direct functional adjustments in response to hypoxia in human in vivo. The mechanism for these changes has not been clearly established, but it may reflect increased tolerance to SCD hypoxic conditions and hypoxia in general.
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PMID:The placental-umbilical unit in sickle cell disease pregnancy: a model for studying in vivo functional adjustments to hypoxia in humans. 1566 92

Leukotrienes play a part in inflammatory response. The unique role of the enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes makes it as therapeutic target for inflammatory conditions like inflammatory bowel disease (IBD). In the present study, by comparing the responses in wild-type mice (5-LOWT) and mice lacking the 5-lipoxygenase (5-LOKO), we investigated the role played by this enzyme in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated 5-LOWT mice, DNBS-treated 5-LOKO mice experienced a reduced rate of the extent and severity of the histological signs of colon injury. After administration of DNBS 5-LOWT mice showed hemorrhagic diarrhea, weight loss and large areas of necrosis in the mucosa of the colon. Neutrophil infiltration was associated with the expression of ICAM-1, VCAM-1, P-selectin, E-selectin that were mainly localized around vessels. Absence of a functional 5-LO resulted in a significant reduction of all the above-described parameters. In particular, we have observed a significant reduction of: (i) the degree of colon injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in staining (immunohistochemistry) for ICAM-1, VCAM-1, P-selectin, E-selectin caused by DNBS in the colon. Similarly, the treatment of 5-LOWT with zileuton (50 mg/kg per os twice a day) resulted in a significant reduction of all the above-described parameters. In addition, in in vitro study a significantly reduced chemotactic response to IL-8 was observed in peripheral blood leukocytes from 5-LOKO in comparison to 5-LOWT polymorphonuclear leukocyte. Similar results were obtained when we analyzed the chemotactic response of 5-LOWT cell incubated for 15 min with zileuton (50 microg/ml). Taken together, our results clearly demonstrate that 5-LO modulates neutrophil infiltration in experimental colitis through the expression of adhesion molecules.
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PMID:5-Lipoxygenase modulates colitis through the regulation of adhesion molecule expression and neutrophil migration. 1582 59

Smoking is a significant risk factor for development of atherosclerosis. However, the pathophysiology of smoking-mediated vessel wall damage is not understood. With tools ranging from analytical chemistry to cell biology, we show that cigarette smoke contains metals that catalyze the direct oxidation of cellular proteins by smoke oxidants. Oxidation of cellular proteins causes a loss of microtubule function, culminating in microtubule depolymerization and proteasome-dependent degradation of alpha-tubulin. As a consequence of the microtubule collapse, cytoskeletal structures as well as intermediate filaments break down, leading finally to a contraction of vascular endothelial cells. We observed a smoke extract-induced, calpain-dependent degradation of the intracellular form of platelet-endothelial cell adhesion molecule 1/CD31, as well as a release of P-selectin/CD62P, IL-6, and IL-8 from endothelial cells into the supernatant. Increased levels of soluble CD62P and IL-6 are well known to be associated with smoking in humans. Increased permeability of the vascular endothelium is a crucial event in atherogenesis. This work highlights the compounds and mechanisms by which cigarette smoke induces leakiness of the vascular endothelium.
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PMID:Cigarette smoke metal-catalyzed protein oxidation leads to vascular endothelial cell contraction by depolymerization of microtubules. 1598 33

Platelet and monocyte activation may contribute to hemolytic anemia, thrombocytopenia and renal failure associated with the hemolytic uremic syndrome (HUS) caused by Escherichia coli O157:H7. Since Shiga toxins (Stxs) and lipopolysaccharide (LPS) from this bacterium are implicated in the pathogenesis of HUS, we examined whether stimulation of THP-1 human monocytic cells by Shiga toxin 2 (Stx2) and LPS can lead to the activation of platelet function. We now show that Stx2 causedTHP-1 cells to release the chemokines IL-8, MDC, and RANTES and that the presence of LPS further stimulated this release. IL-8 was produced in greatest amount and was an effective co-agonist for inducing platelet aggregation. Primary human monocytes also released large amounts of IL-8 in response to LPS and Stx2. Factors released byTHP-1 cells exposed to Stx2 and LPS activated platelet function as evidenced by increased aggregation, serotonin secretion, P-selectin exposure and by the formation of stable platelet-monocyte aggregates. Our data therefore show that monocytes exposed to E.coli-derived Stx2 and LPS release factors which activate platelet function.
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PMID:Shiga toxin 2 and lipopolysaccharide cause monocytic THP-1 cells to release factors which activate platelet function. 1636 2

Peripheral polymorphonuclear leukocytes (PMNL) in hemodialysis (HD) patients are primed, continually releasing and exposing the vascular endothelium to soluble factors such as reactive oxygen species and inflammatory mediators. To mimic the close proximity between PMNL and the endothelial monolayer and to monitor and characterize the influence of soluble mediators released from PMNL, we developed a novel cocultivation system using primary human umbilical vein endothelial cell (HUVEC) cultures and PMNL, with a sieve separating the two cell types to prevent direct adhesive effects. PMNL (10(6)) from HD patients or from healthy normal controls were cocultivated with HUVEC (10(5)) for 15 min, and endothelial cell injury was assessed by HUVEC morphology, cell detachment, and apoptosis. Proinflammatory changes were estimated by expression of HUVEC adhesion molecule P-selectin and by endothelial IL-8 and endothelial nitric oxide synthase mRNA. The levels of intracellular tissue factor reflected the procoagulant state, whereas NADPH oxidase activity served as an indicator for prooxidative changes in HUVEC. Mediators released from the primed PMNL triggered activation/dysfunction of endothelial cells, causing 1) an increase in endothelial cell detachment and apoptosis, 2) a proinflammatory state manifested by increased IL-8 mRNA expression and P-selectin on the endothelial surface, 3) activation of endothelial NADPH oxidase, 4) an increase in endothelial cell tissue factor that directly correlated with PMNL priming index, and 5) a decrease in endothelial nitric oxide synthase mRNA. Our data support a pathogenic link between PMNL priming and endothelial dysfunction, suggesting that PMNL priming is a potential new nontraditional risk factor for the development of atherosclerosis.
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PMID:Priming of polymorphonuclear leukocytes: a culprit in the initiation of endothelial cell injury. 1638 91

The clinical picture of severe acute respiratory syndrome (SARS) is characterized by pulmonary inflammation and respiratory failure, resembling that of acute respiratory distress syndrome. However, the events that lead to the recruitment of leukocytes are poorly understood. To study the cellular response in the acute phase of SARS coronavirus (SARS-CoV)-host cell interaction, we investigated the induction of chemokines, adhesion molecules, and DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin) by SARS-CoV. Immunohistochemistry revealed neutrophil, macrophage, and CD8 T-cell infiltration in the lung autopsy of a SARS patient who died during the acute phase of illness. Additionally, pneumocytes and macrophages in the patient's lung expressed P-selectin and DC-SIGN. In in vitro study, we showed that the A549 and THP-1 cell lines were susceptible to SARS-CoV. A549 cells produced CCL2/monocyte chemoattractant protein 1 (MCP-1) and CXCL8/interleukin-8 (IL-8) after interaction with SARS-CoV and expressed P-selectin and VCAM-1. Moreover, SARS-CoV induced THP-1 cells to express CCL2/MCP-1, CXCL8/IL-8, CCL3/MIP-1alpha, CXCL10/IP-10, CCL4/MIP-1beta, and CCL5/RANTES, which attracted neutrophils, monocytes, and activated T cells in a chemotaxis assay. We also demonstrated that DC-SIGN was inducible in THP-1 as well as A549 cells after SARS-CoV infection. Our in vitro experiments modeling infection in humans together with the study of a lung biopsy of a patient who died during the early phase of infection demonstrated that SARS-CoV, through a dynamic interaction with lung epithelial cells and monocytic cells, creates an environment conducive for immune cell migration and accumulation that eventually leads to lung injury.
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PMID:Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro. 1650 Oct 78

Reperfusion after ischemic conditions induces massive endothelial cell (EC) activation, an initial step of reperfusion injury. Reperfusion is characterized by reoxygenation, realkalinization and a localized increase of inflammatory stimuli. In this study, we focused on the influence of extracellular realkalinization on human umbilical vein endothelial cell (HUVEC) activation. We examined intracellular pH (pH(in)) and intracellular free calcium concentration ([Ca(2+)](in)), a second messenger known to mediate von Willebrand factor (VWF) exocytosis in endothelium, upon realkalinization. Furthermore, we measured the agonist-stimulated exocytosis of VWF, Interleukin-8 and soluble P-selectin (sP-Selectin) as markers of EC activation. To verify a morphological correlate of EC activation, we finally observed platelet-endothelial adherence during realkalinization using shear flow. Realkalinization of HUVEC was simulated by switching from bicarbonate buffered Ringer solution of an acidotic pH(ex) of 6.4 to a physiologic pH(ex) of 7.4. Extracellular realkalinization was accompanied by pH(in) recovery from 6.5 to 7.2 within 10 min. Application of cariporide, an inhibitor of the Na(+)/H(+) exchanger subtype 1 (NHE), during extracellular realkalinization significantly delayed the early kinetics of intracellular realkalinization. Histamine stimulated [Ca(2+)](in) was significantly increased upon realkalinization compared to control cells. Also agonist-stimulated release of VWF, Interleukin-8 and sP-Selectin was massively enhanced during pH(in) recovery in comparison to control. Furthermore, we observed an increased platelet binding to endothelium. Interestingly, each of these realkalinization-induced effects were significantly reduced by early application of cariporide. Therefore, delay of acute NHE-dependent pH(in) recovery may represent a promising mechanism for inhibition of EC activation upon reperfusion.
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PMID:Delay of acute intracellular pH recovery after acidosis decreases endothelial cell activation. 1716 69

The recent molecular characterization and sequencing of equine P-selectin (ePsel), and its glycoprotein ligand, P-selectin glycoprotein ligand-1 (PSGL-1), have provided the tools for further investigation into their role in leukocyte trafficking. Here, we report the generation of a genetically engineered chimeric protein (ePsel-IgG) in which the equine P-selectin lectin and epithelial growth factor (EGF) domains were covalently linked to the equine IgG1 heavy chain constant region. The soluble ePsel-IgG was observed to bind to equine monocytes by confocal microscopy and flow cytometry. Furthermore, equine monocytes bound to immobilized ePsel-IgG in a time course and dose dependent manner. Not only did ePsel-IgG act as an adhesion molecule, it was also found to activate ERK1/2 kinase and induce IL-8 mRNA expression in equine monocytes. That all of the aforementioned ePsel-IgG-induced cell binding and cell signaling were abolished by the addition of EDTA, suggested that ePsel-IgG chimera mediated events occurred via the P-selectin ligand, PSGL-1. We were able to demonstrate that 78% of equine monocytes cross-reacted with anti-human HECA-452 antibody, which recognizes the sialy-Lewis X (sLex) epitope, a well-known carbohydrate binding site on human PSGL-1. Pre-incubation of equine PBMC with neuraminidase or O-sialoglycoprotein endopeptidase (OSGP) reduced ePsel-IgG monocyte binding to 36% or 60%, respectively. Taken together, these data suggest that there might be two ligand recognition sites on P-selectin, one of which recognizes sLex and another which recognizes P-selectin ligand core protein. The ePsel-IgG chimera can be a useful as a reagent for further studies on the role of equine P-selectin and signal transduction in inflammatory events in horse.
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PMID:Cloning and functional characterization of recombinant equine P-selectin. 1730 78


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