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)

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor involved in various processes including the inflammation and carcinogenesis. The aim of the present study was 1) to examine the mRNA and protein expression of PPARgamma in gastric cancer (GC); 2) to evaluate the effect of PPARgamma ligand (ciglitazone) on the proliferation and apoptosis of GC cell line; and 3) to assess the levels of gastric tissue proinflammatory cytokines, IL-1beta and IL-8, and plasma gastrin in GC patients before and after Helicobacter pylori (H. pylori) eradication. The trial material included 30 H. pylori-negative controls and 30 sex- and age-matched GC patients without or with H. pylori before and after its eradication. Expression of tissue PPARgamma, tissue levels of IL-1beta and IL-8, and plasma concentration of gastrin were significantly higher in H. pylori-positive GC compared to controls, but H. pylori eradication significantly reduced these parameters. Kato III cells incubated with alive H. pylori upregulated PPARgamma expression and ciglitazone inhibited cell proliferation and induced apoptosis. PPARgamma, proinflammatory cytokines and plasma gastrin appear to be implicated in H. pylori-related gastric carcinogenesis and PPARgamma agonists may have potential in cancer therapy.
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PMID:Implication of peroxisome proliferator-activated receptor gamma and proinflammatory cytokines in gastric carcinogenesis: link to Helicobacter pylori-infection. 1549 68

Thiazolidinediones (TZDs) are pharmacological ligands of the peroxisome proliferator-activated receptor (PPAR)-gamma that are extensively used in the treatment of type II diabetes. Recently, an anti-inflammatory potential for TZDs has been suggested, based on observations that these compounds may inhibit pro-inflammatory cytokine expression in vitro and may attenuate the inflammatory response in vivo. Here, we show that the TZDs rosiglitazone (RSG) and troglitazone (TRO) do not inhibit the inflammatory response to tumor necrosis factor (TNF)-alpha in various epithelial cell types. On the contrary, both RSG and TRO significantly potentiated TNF-alpha-induced production of granulocyte/macrophage-colony-stimulating factor, interleukin (IL)-6 and/or IL-8 in these cells. This increase in pro-inflammatory cytokine expression was functionally significant as supernatants from cells co-treated with TNF-alpha and TZDs displayed increased neutrophil pro-survival activity when compared with supernatants from cells treated with TNF-alpha alone. Additionally, it was shown that TZDs enhance cytokine expression at the transcriptional level, but that the pro-inflammatory effects of TZDs are independent on PPARgamma, nuclear factor kappaB or mitogen-activated protein kinase activation. Our study shows that TZDs may potentiate the inflammatory response in epithelial cells, a previously unappreciated effect of these compounds.
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PMID:Pro-inflammatory properties for thiazolidinediones. 1562 78

15-Deoxy delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an activator of peroxisome proliferator-activated receptor (PPAR)-gamma and -delta, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, proinflammatory cytokines and prostaglandins have been identified as playing key roles in the maintenance of pregnancy and the onset of labor. We investigated and compared the early (<3 h) effects of 15d-PGJ(2) with rosiglitazone (PPAR-gamma ligand) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516) (PPAR-delta ligand) on interleukin (IL)-1beta-induced prostaglandin and cytokine production by amnion-derived WISH cells. We show that 15d-PGJ(2) exerts differential effects depending on concentration. At low concentrations (<0.1 microM), 15d-PGJ(2) inhibited IL-1beta-stimulated prostaglandin E(2) (PGE(2)) but not cytokine (IL-6/IL-8) production or cyclooxygenase-2 (COX-2) expression. This effect was attenuated by a PPAR-gamma inhibitor [2-chloro-5-nitro-N-phenyl-benzamide (GW9662)], by transfection with a dominant-negative PPAR construct, and was reproduced by the PPAR-gamma ligand rosiglitazone. At higher concentrations (1-10 microM), 15d-PGJ(2) inhibited IL-1beta-stimulated PGE(2) and cytokine production and COX-2 expression, and this effect was not blocked by GW9662. Rosiglitazone at high concentrations (1-10 microM) stimulated PGE(2) production in the absence or presence of the dominant-negative PPAR. The PPAR-delta ligand GW501516 also inhibited IL-1beta-stimulated PGE(2) production but only at high concentrations (1 microM). IL-1beta-induced nuclear factor-kappaB (NF-kappaB) DNA binding activity was significantly inhibited by 15d-PGJ(2) (10 microM) and GW501516 (1 microM) but increased with 10 microM rosiglitazone. We conclude that 1) at low concentrations, 15d-PGJ(2) acts through a PPAR-gamma signaling pathway; b) at higher concentrations, its actions are mediated most likely through other pathways such as activation of PPAR-delta and/or inhibition of NF-kappaB; and 3) rosiglitazone exerts PPAR-independent effects at high concentrations (>1 microM).
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PMID:Nanomolar and micromolar effects of 15-deoxy-delta 12,14-prostaglandin J2 on amnion-derived WISH epithelial cells: differential roles of peroxisome proliferator-activated receptors gamma and delta and nuclear factor kappa B. 1582 Nov 50

We previously demonstrated that trans-10, cis-12 conjugated linoleic acid (CLA) reduced the triglyceride content of human adipocytes by activating mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling via interleukins (IL) 6 and 8. However, the upstream mechanism is unknown. Here we show that CLA increased (>or=6 h) the secretion of IL-6 and IL-8 in cultures containing both differentiated adipocytes and stromal vascular (SV) cells, non-differentiated SV cells, and adipose tissue explants. CLA isomer-specific induction of IL-6 and tumor necrosis factor-alpha was associated with the activation of nuclear factor kappaB (NFkappaB) as evidenced by 1) phosphorylation of IkappaBalpha, IkappaBalpha kinase, and NFkappaB p65, 2) IkappaBalpha degradation, and 3) nuclear translocation of NFkappaB. Pretreatment with selective NFkappaB inhibitors and the MEK/ERK inhibitor U0126 blocked CLA-mediated IL-6 gene expression. Trans-10, cis-12 CLA suppression of insulin-stimulated glucose uptake at 24 h was associated with decreased total and plasma membrane glucose transporter 4 proteins. Inhibition of NFkappaB activation or depletion of NFkappaB by RNA interference using small interfering NFkappaB p65 attenuated CLA suppression of glucose transporter 4 and peroxisome proliferator-activated receptor gamma proteins and glucose uptake. Collectively, these data demonstrate for the first time that trans-10, cis-12 CLA promotes NFkappaB activation and subsequent induction of IL-6, which are at least in part responsible for trans-10, cis-12 CLA-mediated suppression of peroxisome proliferator-activated receptor gamma target gene expression and insulin sensitivity in mature human adipocytes.
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PMID:Conjugated linoleic acid promotes human adipocyte insulin resistance through NFkappaB-dependent cytokine production. 1615 93

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

Essential fatty acids are not only energy-rich molecules; they are also an important component of the membrane bilayer and recently have been implicated in induction of fatty acid synthase and other genes. Using gene chip analysis, we have found that arachidonic acid, an omega-6 fatty acid, induced 11 genes that are regulated by nuclear factor-kappaB (NF-kappaB). We verified gene induction by omega-6 fatty acid, including COX-2, IkappaBalpha, NF-kappaB, GM-CSF, IL-1beta, CXCL-1, TNF-alpha, IL-6, LTA, IL-8, PPARgamma, and ICAM-1, using quantitative reverse transcription-PCR. Prostaglandin E(2) (PGE(2)) synthesis was increased within 5 minutes of addition of arachidonic acid. Analysis of upstream signal transduction showed that within 5 minutes of fatty acid addition, phosphatidylinositol 3-kinase (PI3K) was significantly activated followed by activation of Akt at 30 minutes. Extracellular signal-regulated kinase 1 and 2, p38 and stress-activated protein kinase/c-Jun-NH(2)-kinase were not phosphorylated after omega-6 fatty acid addition. Thirty minutes after fatty acid addition, we found a significant 3-fold increase in translocation of NF-kappaB transcription factor to the nucleus. Addition of a nonsteroidal anti-inflammatory drug (NSAID) caused a decrease in COX-2 protein synthesis, PGE(2) synthesis, as well as inhibition of PI3K activation. We have previously shown that NSAIDs cause an inhibition of arachidonic acid-induced proliferation; here, we have shown that arachidonic acid-induced proliferation is also blocked (P < 0.001) by PI3K inhibitor LY294002. LY294002 also significantly inhibited the arachidonic acid-induced gene expression of COX-2, IL-1beta, GM-CSF, and ICAM1. Taken together, the data suggest that arachidonic acid via conversion to PGE(2) plays an important role in stimulation of growth-related genes and proliferation via PI3K signaling and NF-kappaB translocation to the nucleus.
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PMID:Arachidonic acid activates phosphatidylinositol 3-kinase signaling and induces gene expression in prostate cancer. 1645 98

Adipose tissue is an active endocrine organ producing a variety of cytokines and chemokines, which may be involved in the deregulation of glucose and lipid homeostasis as well as in the inflammatory state observed in obesity. We have shown previously that differentiated human adipocytes secrete a variety of cytokines which are able to induce skeletal muscle insulin resistance. However, the regulation of these factors by anti-diabetic drugs has remained mainly undefined. Secretion of IL-6, IL-8, MIP-1alpha/beta, and MCP-1 by adipocytes was found to be downregulated by adiponectin. In parallel to adiponectin, the AMPK activator AICAR also decreased the secretion of most of the measured cytokines including IL-6 and MIP-1alpha/beta but not IL-8. In contrast, the thiazolidinedione troglitazone only slightly reduced cytokine secretion despite increasing the phosphorylation of AMPK. In conclusion, we show that adipocyte secretion is strongly inhibited by the anti-diabetic adipocyte hormone adiponectin, an effect that can also be mimicked by the AMPK activator AICAR. However, the PPARgamma agonist troglitazone is much less effective in reducing cytokine secretion.
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PMID:Cytokine secretion by human adipocytes is differentially regulated by adiponectin, AICAR, and troglitazone. 1656 50

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

Keeping in view the fact that peroxisome-proliferators activated receptors-PPARs (alpha,gamma) play a crucial role in atherogenic inflammation, the present study was addressed to explore as to how selective and specific PPAR-gamma gene silencing within human mononuclear cells affects genes involved in lipid metabolism and innate immune process. Such a study revealed that with respect to control cells, the PPAR-gamma knock-out cells exhibited significant reduction in the expression of genes coding for PPAR- alpha, CD-36, LDL-R as well as significant increase in the expression of genes coding for IL-4, IL-8, IFN-gamma, CX3CR1, hTERT. However, the expression of genes coding for LXR-alpha and Receptor-C( k ) could not be detected in PPAR-gamma knock-out cells. Based on these results, we propose that PPAR-gamma gene has the inherent capacity to influence the lipid mediated inflammation process in atherosclerotic lesions.
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PMID:Functional genomics of PPAR-gamma in human immunomodulatory cells. 1663 34

Recent data suggest that proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. However, characterization of the cell types involved in inflammation and how these cells promote insulin resistance in human adipocytes are unclear. We simulated acute inflammation using the endotoxin lipopolysaccharide (LPS) to define the roles of nonadipocytes in primary cultures of human adipocytes. LPS induction of the mRNA levels of proinflammatory cytokines (e.g. IL-6, TNF-alpha, and IL-1beta) and chemokines (e.g. IL-8, monocyte chemoattractant protein-1) occurred primarily in the nonadipocyte fraction of newly differentiated human adipocytes. Nonadipocytes were characterized as preadipocytes based on their abundant mRNA levels of preadipocyte markers preadipocyte factor-1 and adipocyte enhancer protein-1 and only trace levels of markers for macrophages and myocytes. The essential role of preadipocytes in inflammation was confirmed by modulating the degree of differentiation in the cultures from approximately 0-90%. LPS-induced proinflammatory cytokine/chemokine expression and nuclear factor-kappaB and MAPK signaling decreased as differentiation increased. LPS-induced cytokine/chemokine expression in preadipocytes was associated with: 1) decreased adipogenic gene expression, 2) decreased ligand-induced activation of a peroxisome proliferator activated receptor (PPAR)-gamma reporter construct and increased phosphorylation of PPARgamma, and 3) decreased insulin-stimulated glucose uptake. Collectively, these data demonstrate that LPS induces nuclear factor-kappaB- and MAPK-dependent proinflammatory cytokine/chemokine expression primarily in preadipocytes, which triggers the suppression of PPARgamma activity and insulin responsiveness in human adipocytes.
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PMID:Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. 1687 30


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