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)

NF-kappaB is a dimeric transcription factor which regulates transcription of a number of different genes including IL-8 and p53. In resting cells NF-kappaB is usually retained in an inactive state in the cytoplasm through binding to a member of the inhibitory kappaB (IkappaB) protein family. The purpose of this study was to determine the effect of 1alpha,25(OH)(2)D(3) on NF-kappaB activation in both unstimulated and stimulated (IL-1alpha) cultured normal human keratinocytes. NF-kappaB DNA binding activity was determined by EMSA using two different oligonucleotides containing the kappaB sequence from either the IL-8 or the p53 promoter. IkappaBalpha and p53 expression was determined by Western blotting and IL-8 expression by ELISA. In unstimulated keratinocytes no NF-kappaB binding to the IL-8 kappaB binding sequence was detectable, whereas stimulation with IL-1alpha (10 ng/ml) led to a significant ( P<0.05) induction of NF-kappaB binding. In contrast NF-kappaB binding to the p53 kappaB binding sequence was detectable in unstimulated cells, although it was significantly increased after IL-1alpha (10 ng/ml) stimulation. Incubation with 1alpha,25(OH)(2)D(3) (10(-8)-10(-7) M) was shown to significantly ( P<0.05) stimulate the expression of IkappaBalpha and in parallel experiments with normal human keratinocytes stimulated with IL-1alpha (10 ng/ml) a significant ( P<0.05) time and dose-dependent decrease in NF-kappaB binding to the IL-8 kappaB binding sequence and in IL-8 expression were seen. A less-pronounced decrease in NF-kappaB binding to the p53 kappaB response element was seen after preincubation with 1alpha,25(OH)(2)D(3) and IL-1alpha stimulation, and it did not result in any change in p53 expression. These results demonstrate that 1alpha,25(OH)(2)D(3) inhibits NF-kappaB binding to the IL-8 kappaB binding sequence more potently than binding to the p53 kappaB binding sequence. We propose that this selectivity may be mediated through an increased expression of IkappaBalpha which leads to an inhibition of specific NF-kappaB subunits resulting in a selective regulation of NF-kappaB-induced gene transcription.
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PMID:1alpha,25(OH)(2)D(3) regulates NF-kappaB DNA binding activity in cultured normal human keratinocytes through an increase in IkappaBalpha expression. 1537 76

Melioidosis is a life-threatening disease caused by Burkholderia pseudomallei. The lung is the most commonly affected organ, resulting in abscess formation in patients with chronic melioidosis. Previous study has shown that B. pseudomallei was able to invade and multiply in epithelial cells. In the present study, we have demonstrated that B. pseudomallei is able to stimulate interleukin 8 (IL-8) production from the human alveolar lung epithelium cell line A549. However, the level of IL-8 production was significantly lower than when the cells were infected with other Gram-negative bacteria such as Salmonella enterica serovar Typhi (S. typhi) which were used for comparison. The degree of IkappaBalpha degradation in the B. pseudomallei-infected cells was lower than that of the S. typhi-infected cells, suggesting that B. pseudomallei is also a poorer cell activator. Inhibition of B. pseudomallei invasion by cytochalasin D did not interfere with either IL-8 production or IkappaBalpha degradation, indicating that bacterial uptake is not required for the production of this chemokine. Thus, it appears that the signalling initiated by the interaction of B. pseudomallei with the epithelial cell surface is sufficient for epithelial cell activation.
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PMID:Burkholderia pseudomallei stimulates low interleukin-8 production in the human lung epithelial cell line A549. 1537 6

Two phenylpropanoids from Bupleurum fruticosum (Apiaceae/Umbelliferae) were shown to inhibit the transcriptional activity induced by PMA or TNFalpha of an NF-kappaB-controlled reporter gene. Western blot experiments indicated that the phenylpropanoids did not prevent IkappaBalpha degradation, suggesting that their molecular target is at a post-IKB degradation level. Both compounds prevented cytokine (IL-1, IL-6, TNF, IL-8) release and prostaglandin E2 synthesis.
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PMID:Phenylpropanoid NF-kappaB inhibitors from Bupleurum fruticosum. 1549 Mar 18

Chronic inflammation is a characteristic feature of aging, and the relationship between cellular senescence and inflammation, although extensively studied, is not well understood. An overlapping pathway screen identified human polynucleotide phosphorylase (hPNPase(old-35)), an evolutionary conserved 3',5'-exoribonuclease, as a gene up-regulated during both terminal differentiation and cellular senescence. Enhanced expression of hPNPase(old-35) via a replication-incompetent adenovirus (Ad.hPNPase(old-35)) in human melanoma cells and normal human melanocytes results in a characteristic senescence-like phenotype. Reactive oxygen species (ROS) play a key role in the induction of both in vitro and in vivo senescence. We now document that overexpression of hPNPase(old-35) results in increased production of ROS, leading to activation of the nuclear factor (NF)-kappaB pathway. Ad.hPNPase(old-35) infection promotes degradation of IkappaBalpha and nuclear translocation of NF-kappaB and markedly increases binding of the transcriptional activator p50/p65. The generation of ROS and activation of NF-kappaB by hPNPase(old-35) are prevented by treatment with a cell-permeable antioxidant, N-acetyl-l-cysteine. Infection with Ad.hPNPase(old-35) enhances the production of interleukin (IL)-6 and IL-8, two classical NF-kappaB-responsive cytokines, and this induction is inhibited by N-acetyl-l-cysteine. A cytokine array reveals that Ad.hPNPase(old-35) infection specifically induces the expression of proinflammatory cytokines, such as IL-6, IL-8, RANTES, and matrix metalloproteinase (MMP)-3. We hypothesize that hPNPase(old-35) might play a significant role in producing pathological changes associated with aging by generating proinflammatory cytokines via ROS and NF-kappaB. Understanding the relationship between hPNPase(old-35) and inflammation and aging provides a unique opportunity to mechanistically comprehend and potentially intervene in these physiologically important processes.
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PMID:Human polynucleotide phosphorylase (hPNPaseold-35): a potential link between aging and inflammation. 1549 72

Human glioma cell lines (G36DeltaEGFR and IN500DeltaEGFR) have been shown to display an enhanced tumorigenic phenotype, when transfected with a constitutively active form of the epidermal growth factor receptor (DeltaEGFR). These cells were transfected with a mutant IkappaBalpha (IkappaBalphaM) that is resistant to phosphorylation and degradation, and hence blocks NF-kappaB activity. Recently, EGFR has been shown to increase the activity of NF-kappaB and to induce angiogenesis. In this report, we asked if IkappaBalphaM gene transfer into human glioma cell lines would inhibit tumorigenicity and angiogenesis in glioma. IkappaBalphaM inhibited in vitro and in vivo expression of vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8). Human glioma xenografts treated with IkappaBalphaM gene transfer exhibited significantly decreased angiogenesis both in an orthotopic and in an ectopic model. The decreased expression of VEGF and IL-8 directly correlated with decreased tumorigenicity, and tumor vascularization. Taken in combination, these results provide strong evidence of IkappaBalphaM's role in regulating glioma angiogenesis even in the presence of constitutive EGFR activation.
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PMID:IkappaBalphaM suppresses angiogenesis and tumorigenesis promoted by a constitutively active mutant EGFR in human glioma cells. 1549 23

The progression of lung disease in cystic fibrosis (CF) is characterized by an exuberant inflammatory response mounted by the respiratory epithelium that is further exacerbated by bacterial infection. Recent studies have demonstrated upregulation of nuclear factor-kappaB (NF-kappaB) in response to infection in genetically modified cell culture models, which is associated with expression of interleukin (IL)-8. Using human airway epithelial cells grown in primary culture, we examined in vitro activation of NF-kappaB in cells isolated from five CF (DeltaF508/DeltaF508) and three non-CF (NCF) patients in response to Pseudomonas aeruginosa. Immunofluorescence, gel-shift, and immunoblot assays demonstrated a rapid translocation of NF-kappaB subunits (p50 and p65) to the nucleus in both CF and NCF cell cultures. However, nuclear extracts from CF cells both before and following P. aeruginosa stimulation revealed elevated NF-kappaB activation compared with NCF cells. Additionally, elevated nuclear levels of the NF-kappaB inhibitor IkappaBalpha were detected in nuclei of CF cells after P. aeruginosa stimulation, but this increase was transient. There was no difference in IL-8 mRNA levels between CF and NCF cells early after stimulation, whereas expression was higher and sustained in CF cells at later times. Our results also demonstrated increased baseline translocation of NF-kappaB to nuclei of primary CF epithelial cell cultures, but intranuclear IkappaBalpha may initially block its effects following P. aeruginosa stimulation. Thus, IL-8 mRNA expression was prolonged after P. aeruginosa stimulation in CF epithelial cells, and this sustained IL-8 expression may contribute to the excessive inflammatory response in CF.
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PMID:NF-kappaB activation and sustained IL-8 gene expression in primary cultures of cystic fibrosis airway epithelial cells stimulated with Pseudomonas aeruginosa. 1551 93

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

Immune system impairment and increased susceptibility to infection among alcohol abusers is a significant but not well-understood problem. We hypothesized that acute ethanol administration would inhibit leukocyte recruitment and endothelial cell activation during inflammation and infection. Using LPS and carrageenan air pouch models in mice, we found that physiological concentrations of ethanol (1-5 g/kg) significantly blocked leukocyte recruitment (50-90%). Because endothelial cell activation and immune cell-endothelial cell interactions are critical regulators of leukocyte recruitment, we analyzed the effect of acute ethanol exposure on endothelial cell activation in vivo using the localized Shwartzman reaction model. In this model, ethanol markedly suppressed leukocyte accumulation and endothelial cell adhesion molecule expression in a dose-dependent manner. Finally, we examined the direct effects of ethanol on endothelial cell activation and leukocyte-endothelial cell interactions in vitro. Ethanol, at concentrations within the range found in human blood after acute exposure and below the levels that induce cytotoxicity (0.1-0.5%), did not induce endothelial cell activation, but significantly inhibited TNF-mediated endothelial cell activation, as measured by adhesion molecule (E-selectin, ICAM-1, VCAM-1) expression and chemokine (IL-8, MCP-1, RANTES) production and leukocyte adhesion in vitro. Studies exploring the potential mechanism by which ethanol suppresses endothelial cell activation revealed that ethanol blocked NF-kappaB nuclear entry in an IkappaBalpha-dependent manner. These findings support the hypothesis that acute ethanol overexposure may increase the risk of infection and inhibit the host inflammatory response, in part, by blocking endothelial cell activation and subsequent immune cell-endothelial cell interactions required for efficient immune cell recruitment.
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PMID:Ethanol blocks leukocyte recruitment and endothelial cell activation in vivo and in vitro. 1552 77

The synthesis and the biological evaluation of a new family diterpenes are presented. The synthetic studies were inspired by the structural framework of acanthoic acid (1) and yielded a family of compounds that were evaluated as anti-inflammatory agents. Among them, compounds 2, 10, 12, and 16 exhibited a very low nonspecific cytotoxicity and inhibited the synthesis of TNF-alpha with greater than 65 % efficacy at low micromolar concentrations. Cytokine-specificity studies revealed that these compounds also inhibited the synthesis of the proinflammatory cytokines IL-1beta and IL-6, while inhibition of IL-1ra and IL-8 synthesis was marginal and only occurred at high concentrations. Further studies, through EMSA and Western blot analyses, indicated that these compounds decreased the extent of phosphorylation of IkappaBalpha; this suggests that they exert their anti-inflammatory profile by inhibiting NF-kappaB-mediated cytokine synthesis. These findings imply that these diterpenes represent promising leads for the development of novel anti-inflammatory agents.
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PMID:A new family of synthetic diterpenes that regulates cytokine synthesis by inhibiting IkappaBalpha phosphorylation. 1554 Feb 20

Lipid oxidation and environmental pollutants are major sources of alpha,beta-unsaturated aldehydes such as acrolein and 4-hydroxynonenal. Acrolein (2-propenal), a major product of organic combustion such as tobacco smoke, represents the most reactive alpha,beta-unsaturated aldehyde, with high reactivity toward nucleophilic targets such as sulfhydryl groups. To investigate how acrolein affects respiratory tract cell activation, we exposed either primary (NHBE) or immortalized human bronchial epithelial cells (HBE1) to 0-25 microM acrolein, and determined effects on basal and tumor necrosis factor-alpha (TNFalpha)-induced production of the chemokine interleukin (IL)-8. Cell exposure to acrolein dose-dependently suppressed IL-8 mRNA levels in HBE1 cells (26, 40, and 79% at 5, 10, and 25 microM acrolein concentrations, respectively) and resulted in corresponding decreases in IL-8 production. Studies of nuclear factor-kappaB (NFkappaB) activation, an essential event in IL-8 production, showed decreased TNFalpha-induced NFkappaB activation by acrolein, illustrated by inhibition of nuclear translocation of NFkappaB and reduced IkappaBalpha degradation. Immunochemical analysis of IkappaB kinase (IKK), a redox-sensitive regulator of NFkappaB activation, indicated direct modification of the IKK beta-subunit by acrolein, suggesting that acrolein may act directly on IKK. In summary, our results demonstrate that acrolein can suppress inflammatory processes in the airways by inhibiting epithelial IL-8 production through direct or indirect inhibitory effects on NFkappaB activation.
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PMID:Inhibition of NFkappaB activation and IL-8 expression in human bronchial epithelial cells by acrolein. 1565 Mar 93


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