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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Butyrate may have paradoxical effects on epithelial cells of similar origin. This study aimed to examine the hypothesis that one mechanism that dictates a cell's response to butyrate is its state of activation. First, the responses to 24 h exposure to butyrate (1-2 mM) of normal and neoplastic human colonic epithelial cells activated by their isolation and primary culture, and of colon cancer cell lines, LIM1215 and Caco-2, were examined. In primary cultures of normal and cancer cells, butyrate had no effect on alkaline phosphatase activities but significantly suppressed urokinase receptor expression by a mean +/- SEM of 30 +/- 12% and 36 +/- 9%, respectively. Interleukin-8 secretion was suppressed by 44 +/- 7% in normal cells (P < 0.05) but was unchanged in cancer cells. In contrast, the cell lines significantly increased alkaline phosphatase activities by >50%, urokinase receptor expression >2-fold and interleukin-8 secretion >3-fold in response to butyrate. Secondly, the effect of butyrate on Caco-2 cells was examined with or without prior exposure to a specific activating stimulus [tumour necrosis factor alpha (TNF alpha)]. Interleukin-8 secretion increased by 145 +/- 23% and 132 +/- 17% on 24 h exposure to 2 mM butyrate or 0.1 microM TNF alpha alone, respectively. However, in cells pre-treated with TNF alpha, butyrate significantly inhibited secretion by 34 +/- 7% below unstimulated levels. The response to butyrate of urokinase receptor, whose expression was not stimulated by TNF alpha, was unchanged. These effects were mimicked by trichostatin A, an inhibitor of histone deacetylase, suggesting that butyrate's paradoxical effects may have been operating by the same mechanism. In conclusion, some of the paradoxical effects of butyrate do not appear to represent inherent differences between normal and transformed cells. Rather, the response may be determined by the state of activation of the cells.
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PMID:Colonic epithelial cell activation and the paradoxical effects of butyrate. 1022 79

Expression of the pleiotropic cytokine interleukin (IL)-6 can be stimulated by the proinflammatory cytokine tumor necrosis factor (TNF) and the microbial alkaloid staurosporine (STS). In this report, the transcriptional mechanisms were thoroughly investigated. Whereas transcription factors binding to the activator protein-1-, cAMP-responsive element-, and CAAT enhancer-binding protein-responsive sequences are necessary for gene activation by STS, nuclear factor (NF)-kappaB alone is responsible and sufficient for inducibility by TNF, which reveals distinct signaling pathways for both compounds. At the cofactor level, cAMP-responsive element-binding protein-binding protein (CBP) or p300 potentiate basal and induced IL-6 promoter activation via multiple protein-protein interactions with all transcription factors bound to the promoter DNA. However, the strongest promoter activation relies on the p65 NF-kappaB subunit, which specifically engages CBP/p300 for maximal transcriptional stimulation by its histone acetyltransferase activity. Moreover, treatment of chromatin-integrated promoter constructions with the histone deacetylase inhibitor trichostatin A exclusively potentiates TNF-dependent (i.e. NF-kappaB-mediated) gene activation, while basal or STS-stimulated IL-6 promoter activity remains completely unchanged. Similar observations were recorded with other natural NF-kappaB-driven promoters, namely IL-8 and endothelial leukocyte adhesion molecule (ELAM). We conclude that, within an "enhanceosome-like" structure, NF-kappaB is the central mediator of TNF-induced IL-6 gene expression, involving CBP/p300 and requiring histone acetyltransferase activity.
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PMID:The nuclear factor-kappaB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. 1054 43

Histone deacetylases play key roles in the regulation of gene transcription. Studies have shown that expression of interleukins IL-2 and IL-8, and insulin-like growth factor 2 (IGF2) are affected by treatment with histone deacetylase inhibitors. We have previously shown that the gene for histone deacetylase 1 (HDAC1) is upregulated following treatment with TSA. The murine homologue of this gene has been reported to be inducible by IL-2. In this study, we have examined the effects IL-2, IGF-II and TSA have on HDAC1 expression in the human hepatocellular carcinoma derived cell line Hep3B. Our results indicate that in contrast to the mouse, HDAC1 is not inducible by IL-2. However, in TSA treated cells, IL-2 and IGF-II were found to act synergistically to reduce TSA induced HDAC1 mRNA levels almost to normal.
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PMID:IGF-II and IL-2 act synergistically to alter HDAC1 expression following treatments with trichostatin a. 1088 Feb 58

It is becoming increasingly clear that epigenetic silencing of gene transcription plays a critical role in the regulation of gene expression in many biological processes. Tight regulation of immunomodulatory substances that are important for the initiation of the inflammatory cascade, such as chemoattractive cytokines, is essential to prevent initiation of unrestrained immune activation. Using the Caco-2 intestinal cell line as a model, we reveal two distinctly different mechanisms by which the gene for the neutrophil chemoattractive cytokine IL-8 is silenced. Nuclear run-on studies, as well as stably transfected reporter and marked minigene constructs, demonstrate that cellular differentiation inhibits immune-activated transcription of the IL-8 gene, a mechanism that is dependent on histone deacetylase activity. Unexpectedly, this silencing mechanism does not involve previously described regulatory elements in the IL-8 promoter but rather cis-acting regions located at a distance from the IL-8 gene locus. Genomic elements distant to the immediate IL-8 locus are also required to silence aberrant basal transcriptional activity of the IL-8 promoter in the absence of immune activation. However, in this case, silencing occurs in a histone deacetylase-independent fashion. These findings were confirmed in transgenic mice in which, in the absence of these elements, aberrant IL-8 gene activity was present primarily in the intestinal tract. Epigenetic silencing of cytokine gene transcription through distant genomic elements is an important level of gene regulation that may be relevant to the pathogenesis of immunologic disease states.
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PMID:Evidence for epigenetic mechanisms that silence both basal and immune-stimulated transcription of the IL-8 gene. 1139 Apr 79

Suberoylanilide hydroxamic acid (SAHA) is a hydroxamic acid-containing hybrid polar molecule; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors of histone deacetylase, exhibits antitumor effects by increasing expression of genes regulating tumor survival, we found that SAHA reduces the production of proinflammatory cytokines in vivo and in vitro. A single oral administration of SAHA to mice dose-dependently reduced circulating TNF-alpha, IL-1-beta, IL-6, and IFN-gamma induced by lipopolysaccharide (LPS). Administration of SAHA also reduced hepatic cellular injury in mice following i.v. injection of Con A. SAHA inhibited nitric oxide release in mouse macrophages stimulated by the combination of TNF-alpha plus IFN-gamma. Human peripheral blood mononuclear cells stimulated with LPS in the presence of SAHA released less TNF-alpha, IL-1-beta, IL-12, and IFN-gamma (50% reduction at 100-200 nM). The production of IFN-gamma stimulated by IL-18 plus IL-12 was also inhibited by SAHA (85% at 200 nM). However, SAHA did not affect LPS-induced synthesis of the IL-1-beta precursor, the IL-1 receptor antagonist, or the chemokine IL-8. In addition, IFN-gamma induced by anti-CD3 was not suppressed by SAHA. Steady-state mRNA levels for LPS-induced TNF-alpha and IFN-gamma in peripheral blood mononuclear cells were markedly decreased, whereas IL-8 and IL-1-beta mRNA levels were unaffected. Because SAHA exhibits antiinflammatory properties in vivo and in vitro, inhibitors of histone deacetylase may stimulate the expression of genes that control the synthesis of cytokines and nitric oxide or hyperacetylate other targets.
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PMID:The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. 1186 42

1. Medium-chain triglyceride (MCT) is often administered to patients with Crohn's disease (CD) or short-bowel syndrome. However, little is known about the effects of medium-chain fatty acids (MCFAs) and MCT on intestinal inflammation. In this study we examined whether caprylic acid, one of the MCFAs, and MCT suppress IL-8 secretion by differentiated Caco-2 cells. 2. We found for the first time that caprylic acid and MCT suppress IL-8 secretion by Caco-2 cells at the transcriptional level when precultured together for 24 h. We also tried to clarify the mechanism of IL-8 gene inhibition by examining the activation of NF-kappaB and other transcription factors by electrophoretic mobility shift assay (EMSA), and found that caprylic acid did not modulate their activation. 3. The result of dual-luciferase assay using Caco-2 cells transfected with IL-8 promoter/luciferase reporter plasmid revealed that caprylic acid inhibited the activation of IL-8 promoter. 4. Similar results were observed when cells were precultured with the well-known potent histone deacetylase inhibitor trichostatin A (TSA). 5. We examined the state of H4 acetylation in IL-8 promoter using the technique known as chromatin immunoprecipitation (Chr-IP). TSA rapidly induced H4 acetylation in IL-8 promoter chromatin, whereas caprylic acid did not. These results suggest that the inhibition of IL-8 gene transcription induced by caprylic acid and TSA does not necessarily require the marked suppression of transcription factors, and the mechanism of inhibition of IL-8 gene transcription may be different between caprylic acid and TSA.
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PMID:Caprylic acid and medium-chain triglycerides inhibit IL-8 gene transcription in Caco-2 cells: comparison with the potent histone deacetylase inhibitor trichostatin A. 1201 Jul 77

Inhibition of histone deacetylation results in increased gene expression. Trichostatin (Ts)A, a specific histone deacetylase (HDAC) inhibitor, up-regulates transcription of some genes but represses expression of others. We quantified histone acetylation in SV-40-transformed lung epithelial cells using flow cytometry. Further, to evaluate the effect of TsA on transcription of genes associated with airway inflammation, we measured interleukin (IL)-8 production by enzyme-linked immunosorbent assay as well as IL-12 transcription by reverse transcription-polymerase chain reaction, in the transformed cells after stimulation with lipopolysaccharide (LPS) in the presence of TsA. Pretreatment of cells with TsA before LPS stimulation induced hyperacetylation of histones (especially in the S phase of the cell cycle), enhanced IL-8 production, and suppressed IL-12p35 and IL-12p40 mRNA accumulation. Thus we have demonstrated a useful way to detect hyperacetylation at the single-cell level, as well as the ability of an HDAC inhibitor to repress genes in epithelial cells.
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PMID:Trichostatin A, a histone deacetylase inhibitor, down-regulates interleukin-12 transcription in SV-40-transformed lung epithelial cells. 1247 Jun 11

Increases in the levels of environmental particulate matter with a diameter of <10 microm diameter (PM(10)) in the air are associated with a variety of adverse health effects, particularly chronic lung and cardiovascular diseases. The expression of many inflammatory genes involves the remodeling of the chromatin structure provided by histone proteins. Histone acetylation causes the unwinding of chromatin structure, therefore allowing transcription factor access to promoter sites. Acetylation is reversible and is regulated by histone acetyltransferases (HATs), which promote acetylation, and deacetylases, which promote deacetylation. PM(10) and H(2)O(2) increased IL-8 protein release from A549 cells after 24-h treatment, and this was enhanced by histone deacetylase inhibition by trichostatin A (cotreatment). PM(10) and H(2)O(2) treatment also increased HAT activity as well as the level of acetylated histone 4 (H4). PM(10) enhanced H4 acetylation that was mediated by oxidative stress as shown by thiol antioxidant inhibition. Acetylation of H4 mediated by PM(10) was associated with the promoter region of the IL-8 gene. These data suggest that remodeling of chromatin by histone acetylation plays a role in PM(10)-mediated responses in the lungs.
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PMID:Histone acetylation regulates epithelial IL-8 release mediated by oxidative stress from environmental particles. 1257 91

Oxidative stress is implicated in lung inflammation due to its effect on proinflammatory gene transcription. Changes in gene transcription depend on chromatin remodeling and the relative activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Alterations in the nuclear histone acetylation:deacetylation balance may result in uncontrolled transcription of specific proinflammatory genes. We studied the effect of hydrogen peroxide (H2O2) and cigarette smoke condensate (CSC) on histone acetylation:deacetylation in human alveolar epithelial cells (A549). H2O2 and CSC significantly increased acetylation of histone H4 proteins and were associated with decreased HDAC activity and HDAC2 levels in A549 cells. Also, the decreased HDAC2 activity was due to protein modification by aldehydes and nitric oxide products. Pretreatment of A549 cells with N-acetyl-l-cysteine attenuated the oxidant-mediated reduction in HDAC activity. Treatment of A549 cells with CSC did not cause nuclear factor-kappaB (NF-kappaB) activation or expression and release of either interleukin (IL)-8 or IL-6. However, H2O2, tumor necrosis factor-alpha (TNF-alpha), and IL-1beta significantly increased NF-kappaB activation and expression of IL-8 compared with control cells. Interestingly, CSC dose dependently inhibited TNF-alpha- and IL-1beta-mediated NF-kappaB activation and IL-8 expression. Thus, H2O2 and CSC enhance acetylation of histone proteins and decrease histone deacetylase activity but differentially regulate proinflammatory cytokine release in alveolar epithelial cells.
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PMID:Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. 1545 40

Binding sites for the dimeric transcription factor activator protein (AP)-1 are found in numerous immunoregulatory and inflammatory genes. The precise mechanisms by which AP-1 activates or represses immune response genes and in particular the roles of individual AP-1 subunits in inflammatory responses are largely unknown. We report here that c-Fos and Fos-related antigen-1 (Fra-1), two inducible components of AP-1, are recruited to the endogenous interleukin (IL)-8 promoter in an IL-1-dependent manner. c-Fos activates IL-8 transcription and synergizes in this effect with p65 NF-kappaB. In contrast, Fra-1 strongly inhibits inducible IL-8 transcription. Fra-1 activation involves its stabilization, ubiquitination, and interaction with histone deacetylase-1. Blockade of MEK1 by PD98059 suppresses c-Fos and Fra-1 expression and, thus, affects two counteractive signals for IL-8 mRNA synthesis simultaneously. This disturbs the inducible recruitment of TATA box-binding protein and RNA polymerase II to the IL-8 promoter. Additional experiments reveal that, in conjunction with p65 NF-kappaB, the MEK1-ERK-dependent synthesis of c-Fos and Fra-1 serves to adjust the overall expression level of IL-8 in response to two of its physiological inducers, IL-1 and epidermal growth factor. Relative to c-Fos, the delayed recruitment of Fra-1 to the IL-8 promoter provides an example how AP-1 subunits may dampen excessive chemokine synthesis.
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PMID:MEK1-dependent delayed expression of Fos-related antigen-1 counteracts c-Fos and p65 NF-kappaB-mediated interleukin-8 transcription in response to cytokines or growth factors. 1561 16


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