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)

A 3- to 8-fold stimulation of interleukin (IL)-8 gene expression by all-trans-retinoic acid (ATRA) was demonstrated in primary cultures of human and monkey tracheobronchial epithelial cells and BEAS-2B serum-sensitive cell line. The effect of ATRA on IL-8 gene expression is dose- and time-dependent. Using cycloheximide, it was observed that new protein synthesis was required for the stimulation. ATRA had no effect on IL-8 messenger RNA stability. A difference in nuclear run-on activity suggests that a transcriptional mechanism is involved in ATRA-enhanced IL-8 gene expression. Promoter-reporter gene transfection studies demonstrated ATRA enhanced IL-8 promoter activity, especially when cells were cotransfected with retinoic acid nuclear receptor-alpha expression vector. Deletion and site-directed mutagenesis analysis revealed the involvement of nuclear factor (NF)-kappaB binding site of the IL-8 gene in ATRA-enhanced promoter activity. Electrophoretic mobility shift assay (EMSA) demonstrated that ATRA enhanced DNA-NF-kappaB complex formation, especially with the p65 subunit. Western blot analysis demonstrated that ATRA did not enhance the protein amount of both the p50 and the p65 subunits in the nuclei. Because ATRA also enhances thioredoxin (TRX) gene expression, the effect of TRX on IL-8 gene expression was examined. IL-8 promoter activity was enhanced in transfected cells by the addition of TRX protein. Treatment of nuclear extracts with TRX also enhanced DNA- NF-kappaB complex formation as observed by EMSA, particularly the p65 subunit. Taking these data together, a novel mechanism is proposed in which ATRA activates promoter activity of IL-8 gene through TRX-dependent NF-kappaB activation.
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PMID:A novel mechanism of retinoic acid-enhanced interleukin-8 gene expression in airway epithelium. 1074 31

Peroxisome proliferator-activated (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPARalpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPARgamma is predominantly expressed in intestine and adipose tissue. PPARgamma triggers adipocyte differentiation and promotes lipid storage. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPARalpha and PPARgamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands: PPARalpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPARgamma ligand. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control. The first evidence for a role of PPARalpha in inflammation control came from the demonstration that PPARalpha deficient mice display a prolonged response to inflammatory stimuli. It was suggested that PPARalpha deficiency results in a reduced beta-oxidative degradation of these inflammatory fatty acid derivatives. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNFalpha and metalloproteases) by negatively interfering with the NF- kappaB, STAT and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte/macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These recent findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis and inflammatory bowel disease.
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PMID:Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. 1108

Retinoid-related orphan receptor alpha (ROR alpha) (NR1F1) is a member of the nuclear receptor superfamily whose biological functions are largely unknown. Since staggerer mice, which carry a deletion in the ROR alpha gene, suffer from immune abnormalities, we generated an adenovirus encoding ROR alpha1 to investigate its potential role in control of the inflammatory response. We demonstrated that ROR alpha is expressed in human primary smooth-muscle cells and that ectopic expression of ROR alpha1 inhibits TNFalpha-induced IL-6, IL-8 and COX-2 expression in these cells. ROR alpha1 negatively interferes with the NF-kappaB signalling pathway by reducing p65 translocation as demonstrated by western blotting, immunostaining and electrophoretic mobility shift assays. This action of ROR alpha1 on NF-kappaB is associated with the induction of IkappaB alpha, the major inhibitory protein of the NF-kappaB signalling pathway, whose expression was found to be transcriptionally upregulated by ROR alpha1 via a ROR response element in the IkappaB alpha promoter. Taken together, these data identify ROR alpha1 as a potential target in the treatment of chronic inflammatory diseases, including atherosclerosis and rheumatoid arthritis.
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PMID:The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response. 1125 22

Mast cells, platelets, and some macrophages are abundant sources of PGD(2) and its active metabolite 15-deoxy-Delta(12,14)-PGJ(2) (15-d-PGJ(2)). The lipid mediator 15-d-PGJ(2) regulates numerous processes, including adipogenesis, apoptosis, and inflammation. The 15-d-PGJ(2) has been shown to both inhibit as well as induce the production of inflammatory mediators such as TNF-alpha, IL-1beta, and cyclooxygenase, mostly occurring via a nuclear receptor called peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Data concerning the effects of 15-d-PGJ(2) on human T cells and immune regulation are sparse. IL-8, a cytokine with both chemotactic and angiogenic effects, is produced by T lymphocytes following activation. Whether 15-d-PGJ(2) can regulate the production of IL-8 in T cells in unknown. Interestingly, 15-d-PGJ(2) treatment of unstimulated T cells induces cell death. In contrast, in activated human T lymphocytes, 15-d-PGJ(2) does not kill them, but induces the synthesis of IL-8. In this study, we report that 15-d-PGJ(2) induced a significant increase in both IL-8 mRNA and protein from activated human T lymphocytes. The induction of IL-8 by 15-d-PGJ(2) did not occur through the nuclear receptor PPAR-gamma, as synthetic PPAR-gamma agonists did not mimic the IL-8-inducing effects of 15-d-PGJ(2). The mechanism of IL-8 induction was through a mitogen-activated protein kinase and NF-kappaB pathway, as inhibitors of both systems abrogated IL-8 protein induction. Therefore, 15-d-PGJ(2) can act as a potent proinflammatory mediator in activated T cells by inducing the production of IL-8. These findings show the complexity with which 15-d-PGJ(2) regulates T cells by possessing both pro- and anti-inflammatory properties depending on the activation state of the cell. The implications of this research also include that caution is warranted in assigning a solely anti-inflammatory role for 15-d-PGJ(2).
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PMID:15-deoxy-Delta 12,14-PGJ2 induces IL-8 production in human T cells by a mitogen-activated protein kinase pathway. 1180 78

Peroxisome proliferator-activated receptor (PPAR)-gamma is a ligand-dependent nuclear receptor that is essential for murine placental development and trophoblast differentiation. In nonreproductive tissues, PPAR-gamma regulates the formation of proinflammatory cytokines. Evidence suggests that many of the observed anti-inflammatory effects of PPAR-gamma are in part caused by antagonizing the activities of the transcription factors, including nuclear factor-kappa B. The aim of this study was to elucidate whether natural [15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2))] and synthetic (troglitazone) PPAR-gamma ligands regulate the secretion of IL-6, IL-8, and TNF-alpha from human intrauterine tissues. Human placenta, amnion, and choriodecidual tissues were incubated in the presence of 10 micro g/ml lipopolysaccharide in the absence (control) or presence of 30 micro M 15d-PGJ(2) (n = 6 independent placenta) or troglitazone (n = 6 independent placentas). After a 6-h incubation, the incubation medium was collected and the release of IL-6, IL-8, and TNF-alpha was quantified by ELISA. Treatment of placental, amnion, and choriodecidual tissues with both 15d-PGJ(2) and troglitazone significantly reduced the release of lipopolysaccharide-stimulated IL-6, IL-8, and TNF-alpha (t test, P < 0.05). Gel shift analyses demonstrated that 15d-PGJ(2), but not troglitazone, suppressed nuclear factor-kappa B DNA-binding activity. The data presented in this study demonstrate that the formation of proinflammatory mediators can be modulated by currently available therapeutic agents and may therefore be of therapeutic potential in human labor.
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PMID:Regulation of proinflammatory cytokines in human gestational tissues by peroxisome proliferator-activated receptor-gamma: effect of 15-deoxy-Delta(12,14)-PGJ(2) and troglitazone. 1236 56

The human ovarian surface epithelium (HOSE) is a common site of gynaecological disease including endometriosis and ovarian cancer, probably due to serial injury-repair events associated with successive ovulations. To comprehend the importance of steroid signalling in the regulation of the HOSE, we used a custom microarray to catalogue the expression of over 250 genes involved in the synthesis and reception of steroid hormones, sterols and retinoids. The array included a subset of non-steroidogenic genes commonly involved in pro-/anti-inflammatory signalling. HOSE cells donated by five patients undergoing surgery for non-malignant gynaecological conditions were cultured for 48 h in the presence and absence of 500 pg/ml interleukin-1alpha (IL-1alpha). Total RNA was reverse-transcribed into biotin-labelled cDNA, which was hybridised to the array and visualised by gold-particle resonance light scattering and charge-coupled device (CCD) camera detection. Results for selected genes were verified by quantitative reverse-transcription PCR. In five out of five cases, untreated HOSE cells expressed genes encoding enzymes required for de novo biosynthesis of cholesterol from acetate and subsequent formation of C21-pregnane and C19-androstane steroids. Consistent with the inability of HOSE cells to synthesise glucocorticoids, oestrogens or 5alpha-reduced androgens de novo, CYP21, CYP19 and 5alpha-reductase were not detected. The only steroidogenic gene significantly up-regulated by IL-1alpha was 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1). Other cytokine-induced genes were IL-6, IL-8, nuclear factor kappaB (NFkappaB) inhibitor alpha, metallothionein-IIA and lysyl oxidase: inflammation-associated genes that respond to glucocorticoids. The only steroidogenic gene significantly suppressed by IL-1alpha was 3betaHSD1. Other genes suppressed by IL-1alpha were aldehyde dehydrogenase (ALDH) 1, ALDH 10, gonadotrophin hormone-releasing hormone receptor, peroxisome proliferation-activated receptor-binding protein (PPAR-bp) and nuclear receptor subfamily 2 group F member 2. These results define a steroidogenic phenotype of cultured HOSE cells and provide a limited expression profile for genes with associated signalling functions. IL-1alpha co-ordinately induces 11betaHSD1 and a panel of glucocorticoid-regulated, inflammation-associated genes in HOSE cells, providing further evidence that cortisol generated by 11betaHSD1 could participate in the local resolution of inflammation associated with ovulation.
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PMID:Steroid signalling in human ovarian surface epithelial cells: the response to interleukin-1alpha determined by microarray analysis. 1552 70

Interaction of eosinophils and bronchial epithelial cells plays a pivotal role in maintaining inflammatory airway disease. Since conjugated linoleic acids (CLA) are suggested to exert anti-inflammatory effects, one purpose of this study was to compare cis-9,trans-11-CLA and trans-10,cis-12-CLA with regard to their influence on the stimulus-induced activation of eosinophils. ECP (eosinophil cationic protein) released in co-culture of stimulated and CLA-treated eosinophils with stimulated bronchial epithelial cells (BEAS-2B) was measured and cis-9,trans-11-CLA was found to be most potent in inhibiting ECP formation. Further, expression of the activation markers CD69 and CD13 induced by various stimuli (TNF-alpha, IL-5, IL-3) was significantly reduced in the presence of cis-9,trans-11-CLA. Subsequently, various concentrations of cis-9,trans-11-CLA vs. linoleic acid (LA, cis-9,cis-12-octadecadienoic acid) were tested for the effect on proliferative response and release of the pro-inflammatory cytokine IL-8 in stimulated BEAS-2B. Addition of cis-9,trans-11-CLA attenuated cell growth and significantly reduced IL-8 production at mRNA and protein levels. In contrast, LA had a slight stimulating effect on proliferation and was less effective in reducing the cytokine release. It was demonstrated that the inhibitory effect of cis-9,trans-11-CLA on IL-8 production is mediated through activation of the nuclear receptor PPARgamma, since blocking the receptor with a selective antagonist (GW9662) restored the stimulus-induced enhancement in IL-8 mRNA expression and protein secretion. PPARgamma has previously been shown to be closely involved in the downregulation of inflammation during hyperresponsiveness related to pulmonary immune responses. Thus, targeting PPARgamma, cis-9,trans-11-CLA might be of therapeutic value in the focus of airway disease while ameliorating inflammatory processes by affecting epithelial and eosinophil functions.
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PMID:Cis-9,trans-11-CLA exerts anti-inflammatory effects in human bronchial epithelial cells and eosinophils: comparison to trans-10,cis-12-CLA and to linoleic acid. 1630 27

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor highly expressed in the colon and playing an anti-inflammatory role through inhibition of the NF-kappaB pathway. Toll-like receptor 4 (TLR4) has been known to mediate LPS-induced cellular signaling through activation of NF-kappaB pathway in intestinal epithelial cells. The aims of this study were to evaluate attenuation of inflammation by PPARgamma in intestinal epithelial cells and to study the possible relation between PPARgamma and TLR4. HT-29 human epithelial cells were stimulated with LPS (20 microg/ml) and PPARgamma ligand, 15d-PGJ2 (10 microM), or with LPS (20 microg/ml) alone for 24 hr. COX-2, IL-8, TLR4, and PPARgamma mRNA expression was assessed by RT-PCR. IL-8 protein levels and TLR4 protein expression were analyzed by ELISA and Western blot, respectively. To evaluate the action mechanisms of PPARgamma ligand, Western blot analysis for IkappaBalpha degradation was performed. Costimulation with LPS and PPARgamma ligand in comparison to LPS stimulation alone (1) decreased COX-2, IL-8 mRNA expression and IL-8 protein secretion, (2) decreased TLR4 mRNA and protein expression, and (3) decreased PPARgamma mRNA expression. PPARgamma ligand delayed LPS-induced IkappaBalpha degradation. These findings suggest that PPAR-gamma ligands suppress inflammation in intestinal epithelial cells. PPARgamma and TLR, these two antagonistic signaling pathways in intestinal epithelial cells may be partially cross-linked.
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PMID:Attenuation of colonic inflammation by PPARgamma in intestinal epithelial cells: effect on Toll-like receptor pathway. 1661 90

Liver-X-Receptor alpha (LXR-alpha) that belongs to nuclear receptor/transcriptional factor family has been recognized to play crucial role in the regulation of lipid metabolism and inflammation. Consequently, the present study was addressed to explore the functional genomics of LXR-alpha within human blood immunomodulatory cells. The results of such a study, which involved LXR-alpha gene silencing through siRNA approach, revealed that: (a) the mRNA expression of genes coding for IL-8, IL-4, CX3CR1, LDLR, hTERT and c-myc was significantly elevated in response to LXR-alpha gene silencing whereas mRNA expression of genes coding for PPARs(alpha, gamma), CD36 and Dicer could not be detected; (b) the expression of Receptor C( k ) protein remained unaffected; (c) the mRNA expression of IFN-gamma gene was down regulated in LXR-alpha knockdown cells. Based upon these results we propose that LXR-alpha gene plays a crucial role in the regulation of innate immunity at the genomic level.
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PMID:Importance of LXR-alpha transcriptome in the modulation of innate immunity. 1675

Dendritic cells (DCs) respond to changes in their lipid environment by altering gene expression and immunophenotype. Some of these alterations are mediated via the nuclear receptor superfamily. However, little is known about the contribution of liver X receptor (LXR) to DC biology. In this study, we present a systematic analysis of LXR, activated by synthetic ligands or naturally occurring oxysterols in developing human monocyte-derived DCs. We found that LXRs are present and can be activated throughout DC differentiation in monocyte- and blood-derived DCs. Administration of LXR-specific natural or synthetic activators induced target gene expression accompanied by increased expression of DC maturation markers, such as CD80 and CD86. In mature DCs, LXR activation augmented the production of inflammatory cytokines IL-12, TNF-alpha, IL-6, and IL-8 and resulted in an increased capacity to activate CD4+ T cell proliferation upon ligation with TLR4 or TLR3 ligands. These effects appear to be underpinned by prolonged NF-kappaB signaling. Supporting such an inflammatory role, we found that LXR positive DCs are present in reactive lymph nodes in vivo. We propose that activation of LXR represents a novel lipid-signaling paradigm that alters the inflammatory response of human DCs.
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PMID:Activation of liver X receptor sensitizes human dendritic cells to inflammatory stimuli. 2041 Apr 89


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