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)

Influenza virus-induced epithelial damage may be mediated, in part, by reactive oxygen intermediates (ROIs). In this study, we investigated the role of ROIs in the influenza virus-induced gene expression of antioxidant enzymes and in the activation of nuclear factor-kappa B (NF-kappa B), an oxidant-sensitive transcriptional factor. Influenza virus infection increased production of intracellular ROIs in A549 pulmonary epithelial cells. Induction of manganese superoxide dismutase (MnSOD) mRNA correlated with increased MnSOD protein and enzyme activity. Influenza virus infection also activated NF-kappa B binding as determined by an electrophoretic mobility shift assay. Pretreatment of A549 cells with N-acetyl-L-cysteine attenuated virus-induced NF-kappa B activation and interleukin (IL)-8 mRNA induction but did not block induction of MnSOD mRNA. In contrast, pyrrolidine dithiocarbamate blocked activation of NF-kappa B and induction of MnSOD and IL-8 mRNAs. Treatment with pyrrolidine dithiocarbamate also markedly decreased virus-induced cell death. Thus oxidants are involved in influenza virus-induced activation of NF-kappa B, in the expression of IL-8 and MnSOD, and in virus-induced cell death.
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PMID:Role of oxidants in influenza virus-induced gene expression. 945 11

We hypothesized that blocking the induction of proinflammatory genes associated with endothelial cell (EC) activation, by inhibiting the transcription factor nuclear factor kappaB (NF-kappaB), would prolong survival of vascularized xenografts. Our previous studies have shown that inhibition of NF-kappaB by adenovirus-mediated overexpression of I kappaB alpha suppresses the induction of proinflammatory genes in EC. However, I kappaB alpha sensitizes EC to TNF-alpha-mediated apoptosis, presumably by suppressing the induction of the NF-kappaB-dependent anti-apoptotic genes A20, A1, manganese superoxide dismutase (MnSOD), and cellular inhibitor of apoptosis 2. We report here that adenovirus mediated expression of a dominant negative C-terminal truncation mutant of p65/RelA (p65RHD) inhibits the induction of proinflammatory genes, such as E-selectin, ICAM-1, VCAM-1, IL-8, and inducible nitric oxide synthase, in EC as efficiently as does I kappaB alpha. However, contrary to I kappaB alpha, p65RHD does not sensitize EC to TNF-alpha-mediated apoptosis although both inhibitors suppressed the induction of the anti-apoptotic genes A20, A1, and MnSOD equally well. We present evidence that this difference in sensitization of EC to apoptosis is due to the ability of p65RHD, but not I kappaB alpha, to inhibit the constitutive expression of c-myc, a gene involved in the regulation of TNF-alpha-mediated apoptosis. These data demonstrate that it is possible to block the expression of proinflammatory genes during EC activation by targeting NF-kappaB, without sensitizing EC to apoptosis and establishes the role of c-myc in controlling induction of apoptosis during EC activation. Finally, these data provide the basis for a potential approach to suppress EC activation in vivo in transgenic pigs to be used as donors for xenotransplantation.
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PMID:Adenovirus-mediated expression of a dominant negative mutant of p65/RelA inhibits proinflammatory gene expression in endothelial cells without sensitizing to apoptosis. 979 84

The effects of WR1065 (SH), the free thiol form of amifostine, on nuclear transcription factor kappaB (NFkappaB) activation, manganese superoxide dismutase (MnSOD) gene expression, and secretion of human vascular endothelial cell growth factor (hVEGF), basic fibroblast growth factor (bFGF), tumor necrosis factor-alpha (TNF-alpha), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, P-selectin, and interleukins IL-1alpha, IL-6, and IL-8 were investigated and compared in human microvascular endothelial (HMEC) and human glioma cells. WR1065 was evaluated at 2 concentrations, 4 mmol/L, ie, its most effective cytoprotective dose, and 40 micromol/L, a noncytoprotective but highly effective dose capable of preventing radiation and chemotherapeutic drug-induced mutations in exposed cells. A 30-minute exposure of HMEC and glioma cell lines U87 and U251 to WR1065 at either of the concentrations resulted in a marked activation of NFkappaB as determined by a gel shift assay, with the maximum effect observed between 30 minutes and 1 hour after treatment. Using a supershift assay, WR1065 exposure was observed to affect only the p50-p65 heterodimer, and not the homodimers or heterodimers containing p52 or c-Rel subunits of NFkappaB. WR1065 was also found to enhance MnSOD gene expression in both HMEC and glioma cells. Gene expression was enhanced 1.8-fold over control levels in HMEC over a period ranging from 12 to 24 hours after the time of maximum activation of NFkappaB. In contrast, MnSOD gene expression in U87 cells rose 3.5 times above control levels over this same period. WR1065 had no effect on the levels of adhesion molecules, cytokines, and growth factors secreted by cells exposed for up to 24 hours as measured by enzyme-linked immunosorbent assay.
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PMID:Differential activation of nuclear transcription factor kappaB, gene expression, and proteins by amifostine's free thiol in human microvascular endothelial and glioma cells. 1191 94

Human parturition is effected by a cascade of factors, of which many are unknown. We aim to identify the genes that are changed by labor in the human myometrium by suppression subtractive hybridization. We also seek to ascertain whether these genes are differentially expressed in the myometrium at the upper or fundal and lower segments of the uterus. Term myometrial tissues were obtained from laboring and nonlaboring women undergoing cesarean section after obtaining informed consent. Total RNA was used in suppression subtractive hybridization (CLONTECH PCR Select) to produce two subtracted cDNA libraries enriched for genes expressed during or before labor, labor and not-in-labor libraries, respectively. Dot blot screening of 400 positive clones, constituting 20% of the two subtracted libraries, revealed 30 differentially expressed clones, 14 of which were up-regulated by labor. Among the 10 known genes that were up-regulated in labor, 6 had apparent immune regulatory and inflammatory roles. Three are well-known inflammatory mediators and modulators that were previously linked with parturition: IL-8, manganese superoxide dismutase (MnSOD), and metalloproteinase-9. Three others, interferon-inducible 1-8d gene, elongation factor 1alpha, and nucleophosmin, have not been previously linked with labor. Constitutively expressed genes, including cyclophilin and alpha-actin, were found to be altered by labor. Quantitative real-time RT-PCR using Taqman probes further confirmed the up-regulation of some of these genes. The amounts of the specific genes assayed were standardized to 18S ribosomal RNA and are expressed as mean +/- SEM. Quantitative real-time RT-PCR showed that IL-8 mRNA rose from 0.003 +/- 0.002 in nonlaboring samples (n = 38) to 0.24 +/- 0.11 (n = 20) in gestational-age-matched spontaneously laboring women (P = 0.035). Similarly, MnSOD rose from 0.11 +/- 0.02 (n = 24) to 1.23 +/- 0.56 (n = 24) in gestational-age-matched women (P = 0.047). Additionally, cyclophilin, often used as a constitutive or housekeeping gene marker, increased from 0.0008 +/- 0.0002 (n = 6) to 0.002 +/- 0.0004 (n = 6; P = 0.008) during labor. Notably, MnSOD mRNA was differentially distributed between the upper (0.63 +/- 0.18) and lower (0.15 +/- 0.05; n = 15; P = 0.022) segments of the uterus, but IL-8 was not (n = 17; P = 0.97). Induced labor further showed significantly higher levels of IL-8 (0.63 +/- 0.21; n = 14) than spontaneous labor (0.22 +/- 0.11; n = 20; P = 0.046), but not MnSOD (P = 0.1). This work identifies novel as well as known genes that were not previously associated with parturition. It extends previous data indicating that there is differential expression of some, but not all genes within the gravid human uterus. Inflammatory genes constitute a major proportion of the known genes found to be up-regulated in labor, lending support to the hypothesis of an inflammatory mechanism for human parturition. This work further indicates that many factors associated with human labor and their complex interactions remain to be elucidated.
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PMID:Human myometrial genes are differentially expressed in labor: a suppression subtractive hybridization study. 1205 Jan 94

Lipopolysaccharide (endotoxin) tolerance is well described in monocytes and macrophages, but is less well characterized in endothelial cells. Because intestinal microvascular endothelial cells exhibit a strong immune response to LPS challenge and play a critical regulatory role in gut inflammation, we sought to characterize the activation response of these cells to repeated LPS exposure. Primary cultures of human intestinal microvascular endothelial cells (HIMEC) were stimulated with LPS over 6-60 h and activation was assessed using U937 leukocyte adhesion, expression of E-selectin, ICAM-1, VCAM-1, IL-6, IL-8, manganese superoxide dismutase, HLA-DR, and CD86. Effect of repeat LPS stimulation on HIMEC NF-kappaB and mitogen-activated protein kinase (MAPK) activation, generation of superoxide anion, and Toll-like receptor 4 expression was characterized. LPS pretreatment of HIMEC for 24-48 h significantly decreased leukocyte adhesion after subsequent LPS stimulation. LPS pretreatment inhibited expression of E-selectin, VCAM-1, IL-6, and CD86, while ICAM-1, IL-8, and HLA-DR were not altered. Manganese superoxide dismutase expression increased with repeated LPS stimulation, with a reduction in intracellular superoxide. NF-kappaB activation was transiently inhibited by LPS pretreatment for 6 h, but not at later time points. In contrast, p44/42 MAPK, p38 MAPK, and c-Jun N-terminal kinase activation demonstrated inhibition by LPS pretreatment 24 or 48 h prior. Toll-like receptor 4 expression on HIMEC was not altered by LPS. HIMEC exhibit endotoxin tolerance after repeat LPS exposure in vitro, characterized by diminished activation and intracellular superoxide anion concentration, and reduced leukocyte adhesion. HIMEC possess specific mechanisms of immunoregulatory hyporesponsiveness to repeated LPS exposure.
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PMID:Mechanisms of endotoxin tolerance in human intestinal microvascular endothelial cells. 1279 22

The objective of this study was to identify cellular and plasma marker(s) of post-I/R (ischaemia/reperfusion) in patients undergoing elective knee surgery where a tourniquet was used to facilitate a bloodless surgical field. We evaluated the inflammatory and redox response by measuring the mRNA levels of ICAM-1 (intercellular cell-adhesion molecule-1), MnSOD (manganese superoxide dismutase), GST-mu (glutathione transferase-mu) and Cu/ZnSOD (copper/zinc superoxide dismutase) in the operated muscle and blood cells pre-operatively (pre-tourniquet) and at various times after reperfusion (tourniquet release). We also measured plasma concentrations of IL (interleukin)-6, IL-8, sICAM-1 (soluble ICAM-1), IL-1beta and TNF-alpha (tumour necrosis factor-alpha) using ELISA. Our results show a strong induction of MnSOD and GST-mu in granulocytes (but not in mononuclear cells or muscle) after reperfusion (2 and 4 h). There was no change in the mRNA level of Cu/ZnSOD after reperfusion. An up-regulation of membrane ICAM-1 in muscle and a decrease in sICAM-1 in plasma were detected after reperfusion. Plasma IL-6 and IL-8 levels (but not TNF-alpha or IL-1beta) increased significantly over baseline at 2 and 4 h after reperfusion. Elevated expression of ICAM-1 in muscle, MnSOD and GST-mu in granulocytes and increased levels of plasma IL-6 and IL-8 may be considered as phase- and cell-specific markers of post-I/R of skeletal muscle in humans.
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PMID:Inflammatory and redox responses to ischaemia/reperfusion in human skeletal muscle. 1528 98

Human adipose-derived stem cells (hASCs) are mesenchymal stem cells with reduced immunogenicity and the capability to modulate immune responses. These properties make hASCs of special interest as therapeutic agents in the settings of chronic inflammatory and autoimmune diseases. Exogenous and endogenous toll-like receptor (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis because of the permanent exposure of the immune system to TLR-specific stimuli. Therefore, hASCs employed in therapy are potentially exposed to TLR ligands, which may result in the modulation of hASC activity and therapeutic potency. In this study, we demonstrate that hASCs possess active TLR2, TLR3, and TLR4, because activation with specific ligands resulted in induction of nuclear factor kappa B-dependent genes, such as manganese superoxide dismutase and the release of interleukin (IL)-6 and IL-8. TLR3 and TLR4 ligands increased osteogenic differentiation, but no effect on adipogenic differentiation or proliferation was observed. Moreover, we show that TLR activation does not impair the immunogenic and immunosuppressive properties of hASCs. These results may have important implications with respect to the safety and efficacy of hASC-based cell therapies.
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PMID:Toll-like receptor-mediated signaling in human adipose-derived stem cells: implications for immunogenicity and immunosuppressive potential. 1906 25

Pulmonary morbidity and mortality resulting from exposure to fine particulate matter (PM) increases with age. The present studies analyzed potential mechanisms underlying increased susceptibility of the elderly to PM using diesel exhaust (DE) as a model. Mice (2 m and 18 m) were exposed to DE (0, 300, and 1000 microg/m(3)) for 3 h once (single) or 3 h/day for 3 days (repeated). Bronchoalveolar lavage fluid (BAL), serum and lung tissue were collected 0 and 24 h later. Exposure to DE resulted in structural alterations in the lungs of older but not younger mice, including patchy thickening of the alveolar septa and inflammatory cell localization in alveolar spaces. These effects were most pronounced 24 h after a single exposure to the higher dose of DE. Significant increases in BAL nitrogen oxides were also noted in older mice, as well as expression of lipocalin 24p3, an oxidative stress marker in the lung with no effects in younger mice. Following DE inhalation, expression of Tumor Necrosis Factor alpha (TNFalpha) was upregulated in lungs of both younger and older mice; however, this was attenuated in older animals. Whereas exposure to DE resulted in increases in lung Interleukin-6 (IL-6) expression in both older and younger mice, IL-8 increased only in older animals. In younger mice, constitutive expression of manganese superoxide dismutase (MnSOD) decreased after DE exposure, while in older mice, constitutive MnSOD was not detectable and DE had no effect on expression of this antioxidant. Taken together, these results suggest that altered generation of inflammatory mediators and MnSOD may contribute to increased susceptibility of older mice to inhaled DE.
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PMID:Pulmonary effects of inhaled diesel exhaust in aged mice. 1972 31

Endothelial progenitor cells (EPC) play a fundamental role in tissue regeneration and vascular repair. Current research suggests that EPC are more resistant to oxidative stress as compared to differentiated endothelial cells. Here we hypothesized that EPC not only possess the ability to protect themselves against oxidative stress but also confer this protection upon differentiated endothelial cells by release of paracrine factors. To test this hypothesis, HUVEC incubated with conditioned medium obtained from early EPC cultures (EPC-CM) were exposed to H2O2 to assess the accumulation of intracellular ROS, extent of apoptosis and endothelial cell functionality. Under oxidative stress conditions HUVEC treated with EPC-CM exhibited substantially lower levels of intracellular oxidative stress (0.2+/-0.02 vs. 0.4+/-0.03 relative fluorescence units, p<0.05) compared to control medium. Moreover, the incubation with EPC-CM elevated the expression level of antioxidant enzymes in HUVEC (catalase: 2.6+/-0.4; copper/zinc superoxide dismutase (Cu/ZnSOD): 1.6+/-0.1; manganese superoxide dismutase (MnSOD): 1.4+/-0.1-fold increase compared to control, all p<0.05). Furthermore, EPC-CM had the distinct potential to reverse the functional impairment of HUVEC as measured by their capability to form tubular structures in vitro. Finally, incubation of HUVEC with EPC-CM resulted in a significant reduction of apoptosis (0.34+/-0.01 vs. 1.52+/-0.12 relative fluorescence units, p<0.01) accompanied by an increased expression ratio of the anti/pro-apoptotic factors Bcl-2/Bax to 2.9+/-0.7-fold (compared to control, p<0.05). Most importantly, neutralization of selected cytokines such as VEGF, HGF, IL-8 and MMP-9 did not significantly reverse the cyto-protective effect of EPC-CM (p>0.05), suggesting that soluble factors secreted by EPC, possibly via broad synergistic actions, exert strong cyto-protective properties on differentiated endothelium through modulation of intracellular antioxidant defensive mechanisms and pro-survival signals.
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PMID:Paracrine factors secreted by endothelial progenitor cells prevent oxidative stress-induced apoptosis of mature endothelial cells. 2022 93

It is well established that exposure to ambient fine particulate matter (PM), defined as PM < or = 2.5 microm in aerodynamic diameter (PM2.5), is associated with increased cardiovascular morbidity and mortality and that elderly persons are particularly susceptible to these effects. We speculated that the increased susceptibility of elderly persons to PM is due to altered production of inflammatory mediators and antioxidants in the lung. We performed pilot studies in an animal model to test this hypothesis. For these studies we used diesel exhaust (DE), a major component of urban PM, as a model. Two groups of male CB6F1 mice, 2 months and 18 months old, (referred to in this report as young and old mice, respectively) were exposed to DE at 300 or 1000 microg/m3 PM (referred to as low- or high-dose DE, respectively), or to filtered air as a control, for one 3-hour period (single exposure) or for 3 hours on each of three consecutive days (repeated exposure). Mice were killed and bronchoalveolar lavage (BAL) fluid, serum, and lung tissue were collected immediately after exposure (0 hours) and 24 hours after the final exposure. After single or repeated exposure to DE, persistent structural alterations and inflammation were observed in the lungs of old mice. These changes consisted of patchy thickening of alveolar septa and an increase in the number of neutrophils and macrophages in alveolar spaces. In the young mice, in contrast, no major alterations in lung histology were noted. In old but not in young mice, significant increases in messenger RNA (mRNA) expression of the oxidative-stress marker lipocalin 24p3 were also observed. In both young and old mice, exposure to DE was associated with increased expression of tumor necrosis factor alpha (TNF-alpha) mRNA in the lung. However, this response was attenuated in old mice. Exposure to high-dose DE resulted in significant increases in interleukin (IL)-6 and IL-8 mRNA expression in the lungs of old animals; these increases persisted for 24 hours. Whereas IL-6 was also up-regulated in young mice after DE exposure, no major effects were evident on the expression of IL-8 mRNA. Expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD) was decreased in lung tissue from young animals after single or repeated exposure to DE. In contrast, constitutive expression of MnSOD was not evident in lungs of old mice, and DE had no effect on the expression of this antioxidant. These preliminary data confirm that old mice are more sensitive to DE than young mice and that increased sensitivity is associated with altered expression of inflammatory cytokines and the antioxidant MnSOD. These aberrations may contribute to the increased susceptibility of old mice to inhaled PM.
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PMID:Pulmonary effects of inhaled diesel exhaust in young and old mice: a pilot project. 2138 34


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