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

Infection-induced malnutrition, the most common form of cytokine-induced malnutrition, results from the actions of proinflammatory cytokines, ie, tumor necrosis factor (TNF) and interleukins 1,6, and 8 (IL-1, IL-6, and IL-8). During acute generalized infections, these cytokines initiate the acute-phase reaction. This reaction is quite stereotyped, and includes fever, malaise, myalgia, headaches, cellular hypermetabolism, and multiple endocrine and enzyme responses. In addition, there is heightened catabolism of muscle proteins and many amino acids; flux of free amino acids into the liver; hepatic synthesis of acute-phase plasma proteins; sequestration of iron and zinc; gluconeo-genesis; insulin resistance; impaired cellular uptake of fatty acids from plasma triglycerides; sizable losses of body nitrogen, potassium, magnesium, phosphate, and zinc; retention of body salt and water; heightened metabolic degradation and/or loss of vitamins; and an activation of the immune system. The pathogenesis of cytokine-induced malnutrition is thus vastly different from the malnutrition caused by uncomplicated starvation. Cytokine-induced malnutrition can have a devastating effect on the immune system and its functions. Although proinflammatory cytokines are found in mucosal fluids, where they contribute to the pathogenesis of inflammatory bowel diseases, it is not known whether cytokines play a role in toxigenic, secretory diarrheas such as cholera, which cause huge losses of body water, electrolytes, and bicarbonate while exhibiting no systemic manifestations of an acute-phase reaction.
 ...
PMID:Herman Award Lecture, 1995: infection-induced malnutrition--from cholera to cytokines. 757 15

The A549 cell line was used to model in vitro the interaction of alveolar epithelium with environmental particulates. Confocal and electron microscopy demonstrated A549 binding and internalization of titanium dioxide (TiO2), iron oxide (Fe2O3), concentrated ambient air particulates (CAPs), and the fibrogenic particle alpha-quartz. Flow cytometry allowed quantitation of particle binding by measuring increased right angle light scatter (RAS) (TiO2) [40 micrograms/mL], Fe2O3 [100 micrograms/mL], alpha-quartz [200 micrograms/mL], or CAPs [40 micrograms/mL] fold increase RAS: 8.1 +/- 0.9, 4.3 +/- 0.4, 2 +/- 0.1, 1.6 +/- 0.1, respectively). With this quantitative assay, binding of particle was found to be calcium-dependent for TiO2 and Fe2O3 (% inhibition, 61.0 +/- 1.9, 40.0 +/- 5.6, respectively), while alpha-quartz binding was calcium-independent. A panel of polyanionic ligands known to inhibit scavenger-type receptors was used to identify binding mechanisms for environmental particulates. Both heparin and polyinosinic acid (polyI), but not the control polyanion chondroitin sulfate, caused marked inhibition of particulate binding by A549 cells (e.g., TiO2 [40 micrograms/mL] binding; polyI, heparin, and chondroitin sulfate: 73.8 +/- 3.5, 75.5 +/- 6.0, 7.5 +/- 6.7% inhibition, respectively; mean +/- SE, n > or = 4), indicating that scavenger receptor(s), albeit those distinct from the heparin-insensitive acetylated-LDL receptor, mediate particulate binding. The particulates ability to stimulate interleukin (IL-8) production in A549 cells was also tested. alpha-quartz, but not TiO2 or CAPs, caused a dose-dependent production of IL-8 (range 1-6 ng/mL), demonstrating a particle-specific spectrum of epithelial cell cytokine (IL-8) response. The results suggest that lung epithelial cell interaction with environmental particles is mediated by distinct receptors and can lead to particle dependent cytokine responses.
 ...
PMID:Lung epithelial cell (A549) interaction with unopsonized environmental particulates: quantitation of particle-specific binding and IL-8 production. 888 55

Despite the many epidemiological studies supporting the contention that ambient air pollution particles can adversely affect human health, there is no clear agreement as to a biologically plausible mechanism which can explain the acute mortality and morbidity associated with exposure to particles less than 10 microm in size. We tested the hypothesis that metals present in an air pollution particle can induce the synthesis and expression of the inflammatory cytokines IL-8, IL-6, and TNFalpha. A residual oil fly ash (ROFA) containing the transition metals vanadium, nickel, and iron was used as a model emission source air pollution particle. Normal human bronchial epithelial (NHBE) cells were exposed for either 2 or 24 hr to 0, 5, 50, or 200 microg/ml ROFA. Concentrations of IL-8, IL-6, and TNF-alpha proteins were measured with commercially available ELISA kits. mRNA for these same cytokines was quantified by RT-PCR. NHBE cells exposed to ROFA produced significant amounts of IL-8, IL-6, and TNF, as well as mRNAs coding for these cytokines. Cytokine production was inhibited by the inclusion of either the metal chelator deferoxamine (1.0 mM) or the free radical scavenger dimethylthiourea (1.0 mM). In addition, vanadium containing compounds, but not iron or nickel sulfates, mimicked the effects of intact ROFA. These results demonstrate that metals present in ROFA may be responsible for production and release of inflammatory mediators by the respiratory tract epithelium and suggest that these mediators may contribute to the toxic effects of particulate air pollutants reported in epidemiology studies.
 ...
PMID:Cytokine production by human airway epithelial cells after exposure to an air pollution particle is metal-dependent. 934 85

Studies are summarized demonstrating that the inflammatory cytokines, interleukin IL-6 and IL-8, play a direct role in asbestos lung diseases and are produced by lung epithelial cells in direct response to the fibers. This response is controlled by changes in the cellular oxidative/state induced by iron present in the fiber through Fenton-type chemistry. As a result of this oxidative stress, the redox sensitive transcription factors, NF-kappaB and NF-IL-6, which help regulate cytokine gene expression, are activated.
 ...
PMID:Asbestos induces inflammatory cytokines in the lung through redox sensitive transcription factors. 1002 65

The human lung accumulates iron with senescence. Smoking escalates the accumulation of iron, and we have demonstrated regional variability in the accumulation of iron in smokers' lungs. Iron has been reported to influence the production of a number of proinflammatory mediators, including human interleukin (IL)-1beta. We postulated that we could (1) demonstrate regional differences in the release of IL-1beta from human alveolar macrophages and (2) influence the production of IL-1beta in human macrophages by altering intracellular iron concentrations. To test these hypotheses, alveolar macrophages were obtained by independent lavage of the upper and lower lobes of healthy volunteers (both smokers and nonsmokers), after which the ability of each population to secrete IL-1beta was quantified, together with their ability to produce tumor necrosis factor-alpha, IL-6, and IL-8. Additionally, we established an in vitro model of "iron-loaded" cells of the human myelomonocytic cell line THP-1 in order to examine more directly the effect of iron and its chelation on the secretion of IL-1beta. We report here that an intracellular, chelatable pool of iron expands with exogenous iron-loading as well as with lipopolysaccharide (LPS) stimulation and appears to suppress transcription of IL-1beta, whereas shrinkage of this pool by early chelation augments transcription of IL-1beta beyond that induced by LPS alone. And finally, we demonstrate a regional relationship in the lung between excess alveolar iron and the production of human alveolar macrophage-derived IL-1beta, suggesting a partnership between iron and inflammation that may have clinical significance, especially in relation to lung diseases with a regional predominance.
 ...
PMID:Iron is a regulatory component of human IL-1beta production. Support for regional variability in the lung. 1087 60

The balance between pro- and antiinflammatory cytokines may be important in malaria presentation and outcome. Malaria tends to be more severe in children than in adults, presumably because partial immunity develops with age. However, the full nature of, and age-related differences in, anti-malarial immunity are unknown. We compared: (1) serum and cell-specific cytokines of patients with acute malaria to those of patients with other acute illnesses and to those of healthy adults and (2) the cytokine responses of parasitemic children and parasitemic adults. Flow cytometry was done on the peripheral blood mononuclear cells of 148 hospitalized children, 161 febrile hospitalized adults, and 20 healthy adults in Malawi, Africa, a malaria-endemic country. Serum cytokines were also assessed for 80 of these patients. Thirty-eight participants were parasitemic with Plasmodium falciparum. Serum interleukin (IL)-10 (an antiinflammatory, immunoregulatory, and type 2 cytokine) levels were higher in malaria patients than in other patients (medians 502 pg/mL vs 16 pg/mL, P = 0.002), and the percentages of various lymphocyte populations making IL-6 (a proinflammatory, type 2 cytokine regulating iron distribution) were lower in malaria patients than in other patients (e.g., for spontaneous production by children's CD8(+) T cells: medians 1.4% vs 33.1%, P = 0.004). For adult patients, the percentages of lymphocytes spontaneously making IL-4 (a type 2 cytokine) were significantly lower in those with malaria than in those without malaria (medians 0.9% vs 2.1%, P = 0.005). The percentages of monocytes spontaneously making IL-8 (a chemotactic, proinflammatory chemokine) were higher in parasitemic children than in parasitemic adults (medians 5.8% vs 1.7%, P = 0.003). A number of cellular proinflammatory, type 1 parameters were significantly higher in all children (with or without malaria) than in all adults; these included the percentages of various lymphocyte populations making IL-6, both IL-6 and interferon-gamma, or IL-8. These data support the importance of IL-10 in malaria parasitemia. Given the lack of an IL-4 (type 2) response, IL-10's primary role may be immunoregulatory rather than type 2 in nature. In this study, the immune response to malaria was more proinflammatory in children than in adults. This difference, if corroborated by other studies, could be related to malaria's greater severity in children.
 ...
PMID:Cytokines and malaria parasitemia. 1146 50

Pentoxifylline, a methylxanthine derivative and nonspecific type 4 phosphodiesterase inhibitor, has been used to improve survival of animals with sepsis and to attenuate lung injury in acute lung inflammation. The purpose of this study was to examine whether pentoxifylline would inhibit the expression of inflammatory cytokines, particularly tumor necrosis factor alpha (TNF), and thereby decrease the pathophysiology of acute porcine pleuropneumonia. E. coli lipopolysaccharide (LPS) and bacterial extracts of A. pleuropneumoniae--induced elevations in TNF mRNA which were fully abrogated by addition of pentoxifylline in both alveolar macrophage and neutrophil cultures. A 30% reduction in the level of LPS-induced interleukin (IL)-1beta mRNA levels also was achieved in macrophages. Pentoxifylline did not affect either IL-1alpha or IL-8 expression in vitro. Pentoxifylline therapy in vivo significantly reduced the number of band neutrophils in swine but did not reduce the pathology associated with pleuropneumonia, including changes in serum zinc, iron, or haptoglobin. Neither did it alter TNF, IL-1, IL-6, or IL-8 expression. Measurement of pentoxifylline and its metabolites in pig sera suggested that efficacious doses of pentoxifylline were probably not achieved in vivo. However, subcutaneous doses of pentoxifylline higher than 25 mg/kg produced transient diarrhea, vomiting, and tremors. These results suggest that pentoxifylline is an effective pharmacological tool for the dissection of cytokine regulation in vitro, but inhibitory concentrations may not be achievable for in vivo pharmacological use in swine.
 ...
PMID:Effects of pentoxifylline on inflammatory cytokine expression and acute pleuropneumonia in swine. 1199 42

Some recent epidemiologic investigations have shown an association between increased incidence of respiratory symptoms and exposure to low levels of particulate matter (PM*) less than 10 microm or less than 2.5 microm in aerodynamic diameter (PM10 and PM2.5, respectively). If particulates are causally involved with respiratory symptoms, it is important to understand which components may be responsible. However, increasing evidence suggests that transition metals present in particles, especially iron, generate reactive oxygen species (ROS) that may be involved in producing some of the observed respiratory symptoms. The hypothesis for this study is twofold: bioavailable transition metals from inhaled airborne particulates catalyze redox reactions in human lung epithelial cells, leading to oxidative stress and increased production of mediators of pulmonary inflammation: and the size, transition metal content, and mineral speciation of particulates affect their ability to cause these effects. This work focused on the relation between physical characteristics of particles (eg, size, bioavailable transition metal content, and mineral speciation) and their ability to generate hydroxyl radicals in cell-free systems and to cause oxidative stress, which results in the synthesis of mediators of pulmonary inflammation in cultured human lung epithelial cells. These relations were studied by comparing size-fractionated, chemically characterized coal fly ash (CFA) produced by combustion of three different coals to obtain milligram quantities of ash. One transition metal, iron, was studied specifically because it is by far the predominant transition metal in CFA. In addition, smaller quantities of particles from gasoline engines, diesel engines, and ambient air were studied. Phosphate buffer soluble fractions from particles from all sources were capable of generating ROS, as measured by production of malondialdehyde (MDA) from 2-deoxyribose. This activity was inhibited over 90% for all particles by the metal chelator N-[5-[3-[(5-aminopentyl)hydroxycarbamoyl]propionamidol-pentyl]-3-[[5-(N-hydroxyacetamido)pentyl]carbamoyl]propionohydroxamic acid (desferrioxamine B, or DF), strongly suggesting that transition metal(s), probably iron, were responsible. Particles from coal or gasoline combustion had greater ability to produce ROS than particles from diesel combustion. Iron was mobilized by citrate (at pH 7.5) from particles of all sources tested; gasoline combustion particles were the only particles not analyzed for iron mobilization because there were not enough particles for the iron mobilization assay. CFA particles were size-fractioned; the amount of iron mobilized by citrate was inversely related to the size of particles and also depended on the source of coal. Iron from the CFA particles was responsible for inducing the iron-storage protein ferritin in cultured human lung epithelial cells (A549 cells). The amount of iron mobilized by citrate was directly proportional to the amount of ferritin induced in the A549 cells. Iron from the CFA was also responsible for inducing the inflammatory mediator interleukin (IL) 8 in A549 cells. Iron existed in several species in the fly ash, but the bioavailable iron was associated with the glassy aluminosilicate fraction, which caused ferritin and IL-8 to be induced in the A549 cells. In crustal dust, another component of urban particulates, iron was associated with oxides and clay but not with aluminosilicates. The crustal dust contained almost no iron that could be mobilized by citrate. Iron could be mobilized from diesel combustion particulates, but at a much lower level than for all other combustion particles. Samples of ambient PM2.5 collected in Salt Lake City over 5-day periods during one month varied widely in the amount of iron that could be mobilized. If bioavailable transition metals (eg, iron) are related to the specific biological responses outlined here, then the potential exists to develop in vitro assays to determine whether particulates of unknown composition and origin can cause effects similar to those observed in this study.
 ...
PMID:Particle characteristics responsible for effects on human lung epithelial cells. 1257 13

Plasma essential trace elements, selenium, copper, zinc, and iron concentrations and the levels of immunoregulatory cytokines, interleukin-1beta (IL-1beta), interleukin-2 receptor (IL-2r), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) were evaluated in patients with cutaneous leishmaniasis (CL) to investigate a possible role of these cytokines on selenium, zinc, copper, and iron homeostasis in CL patients. Plasma albumin levels were measured as an index of nutritional status. Plasma selenium, zinc, and iron concentrations, and IL-2r levels were significantly lower, and copper concentrations and IL-1beta, IL-8, IL-6 and TNF-alpha levels were significantly higher in patients with CL than those of healthy controls. There was no significant difference in plasma albumin levels between two groups. There were positive important correlations between plasma selenium and IL-2r, copper and IL-6, and copper and IL-1beta, and negative correlations between selenium and IL-8, iron and TNF-alpha, and zinc and IL-1beta contents in patients with CL. Our results showed that plasma trace element contents change in patients with CL. These changes may not be a result of a specific deficiency from dietary inadequacies or imbalances, but, probably, a result of a part of the defense strategies of an organism that is regulated by immunoregulatory cytokines.
 ...
PMID:Associations among plasma selenium, zinc, copper, and iron concentrations and immunoregulatory cytokine levels in patients with cutaneous leishmaniasis. 1266 25

Vascular cell adhesion molecule (VCAM)-1 expression may be coupled to redox-sensitive regulatory pathways, and iron may play a role in generation of reactive oxygen species that participate in these signaling pathways. To investigate the role of iron in TNF alpha-induced VCAM-1 gene expression, human dermal microvascular endothelial cells (HDMEC) were stimulated with TNF alpha in the presence of iron chelators and examined for expression of VCAM-1. The iron chelators dipyridyl (DP) and desferoxamine (DFO) inhibited VCAM-1 protein and mRNA induction in a concentration- and time-dependent manner. The induction of VCAM-1 was not inhibited by nonmetal binding reactive oxygen species (ROS) scavengers, implying a direct effect of iron in the expression of these adhesion molecules. The effect of iron was mediated at the level of gene transcription since pretreatment with DP abrogated the TNF alpha-mediated up-regulation of VCAM-1 heterogeneous nuclear RNA. Pretreatment of HDMEC with DP prior to TNFalpha treatment had no effect on p65 nuclear localization, DNA binding, or serine phosphorylation. DP pretreatment inhibited TNF alpha- and IFN gamma-mediated interferon regulatory factor 1 (IRF-1) protein expression, although restoration of IRF-1 expression failed to reconstitute VCAM-1 expression. DP treatment also blocked VCAM-1 induction in human umbilical vein endothelium and blocked induction of a host of NF-kB activated genes in HDMEC including ICAM-1, IL-8, and tissue factor. I kappa B alpha, an NF-kappa B inducible and constitutively accessible gene not requiring chromatin remodeling for transcription, was not affected by DP treatment. These data suggest that iron plays a critical role in TNF alpha mediated VCAM-1 induction in HDMEC, and the target for iron effects may be IRF-1, NF-kappa B, and potentially chromatin remodeling.
 ...
PMID:Iron chelators inhibit VCAM-1 expression in human dermal microvascular endothelial cells. 1470 35


1 2 3 4 5 6 7 8 9 10 Next >>