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)

Dietary nucleotides have been reportedly beneficial, especially for infants, since they positively influence lipid metabolism, immunity, and tissue growth, development and repair. Rapidly proliferating tissues, such as the immune system or the intestine are not able to fulfil the needs of cell nucleotides exclusively by de novo synthesis and they preferentially utilize the salvage pathway recovering nucleosides and nucleobases from blood and diet. In the present review we describe the modulatory effect of dietary nucleotides on the immune system together with some of their effects on gut-associated lymphoid tissue. Dietary nucleotides influence lymphocyte maturation, activation and proliferation. Likewise, they affect the lymphocyte subset populations in both the small intestine and blood. Moreover, they are involved in enhancing macrophage phagocytosis and delayed hypersensitivity as well as allograft and tumour responses. In addition, they contribute to the immunoglobulin response in early life, having a positive effect on infection. In fact the incidence and duration of acute diarrhoea is lower in infants fed supplemented-nucleotide formulas. The molecular mechanisms by which dietary nucleotides modulate the immune system are practically unknown. Dietary nucleotides have been shown to enhance the production and the genetic expression of IL-6 and IL-8 by foetal small intestinal explants. Dietary nucleotides may influence protein biosynthesis as well as signal membrane transduction mediated by the interaction of exogenous nucleosides and their receptors may also contribute to modulate the expression of a number of genes, some of which can directly affect the levels of intestinal cytokines.
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PMID:Modulation of the immune response mediated by dietary nucleotides. 1214 52

During inflammatory bowel disease and intestinal ischemia, epithelial cells of the gut mucosa produce various inflammatory mediators, including the chemokine interleukin (IL-8). This IL-8 produced by intestinal epithelial cells has recently been implicated as a contributory factor to the deleterious inflammatory process resulting in colitis during inflammatory bowel disease or multiple organ failure following shock and trauma. Recent evidence suggests that the transcription factor nuclear factor kappaB (NF-kappaB) is a central regulator of IL-8 gene expression. In the present paper we investigated the effect of pharmacological inhibition of NF-kappaB with pyrrolidinedithiocarbamate (PDTC) on IL-1beta-induced IL-8 production by the human intestinal epithelial cell line HT-29. Pretreatment of cells with PDTC (3-1000 microM) dose-dependently attenuated IL-8 production. Furthermore, PDTC (100 microM) suppressed the accumulation of IL-8 mRNA. PDTC inhibited the activation of NF-kappaB, because PDTC suppressed both NF-kappaB DNA binding and NF-kappaB-dependent transcriptional activity. Taken together, our data demonstrate that NF-kappaB inhibition with PDTC decreases IL-8 production by intestinal epithelial cells.
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PMID:Pyrrolidinedithiocarbamate inhibits NF-kappaB activation and IL-8 production in intestinal epithelial cells. 1250 95

Intestinal epithelial cells (IEC) interact with a high density of Gram-positive bacteria and are active participants in mucosal immune responses. Recognition of Gram-positive organisms by Toll-like receptor (TLR)2 induces proinflammatory gene expression by diverse cells. We hypothesized that IEC are unresponsive to Gram-positive pathogen-associated molecular patterns and sought to characterize the functional responses of IEC to TLR2-specific ligands. Human colonic epithelial cells isolated by laser capture microscopy and IEC lines (Caco-2, T84, HT-29) were analyzed for expression of TLR2, TLR6, TLR1, and Toll inhibitory protein (Tollip) mRNA by RT-PCR and quantitative real-time PCR. Response to Gram-positive bacterial ligands was measured by NF-kappa B reporter gene activation and IL-8 secretion. TLR2 protein expression was analyzed by immunofluorescence and flow cytometry. Colonic epithelial cells and lamina propria cells from both uninflamed and inflamed tissue demonstrate low expression of TLR2 mRNA compared with THP-1 monocytes. IECs were unresponsive to TLR2 ligands including the staphylococcal-derived Ags phenol soluble modulin, peptidoglycan, and lipotechoic acid and the mycobacterial-derived Ag soluble tuberculosis factor. Transgenic expression of TLR2 and TLR6 restored responsiveness to phenol soluble modulin and peptidoglycan in IEC. In addition to low levels of TLR2 protein expression, IEC also express high levels of the inhibitory molecule Tollip. We conclude that IEC are broadly unresponsive to TLR2 ligands secondary to deficient expression of TLR2 and TLR6. The relative absence of TLR2 protein expression by IEC and high level of Tollip expression may be important in preventing chronic proinflammatory cytokine secretion in response to commensal Gram-positive bacteria in the gut.
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PMID:Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. 1253 1

Campylobacter jejuni can cause an enteritis that is associated with an acute inflammatory response at the gut epithelial surface. The signals inducing inflammation are unknown. C. jejuni can penetrate the intestinal epithelial barrier and may then interact with leucocytes, potentially inducing proinflammatory responses. To investigate this, we studied the interaction of C. jejuni with the human monocytic cell line THP-1 and show that a range of proinflammatory cytokines and chemokines is induced. These include interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-8, and tumor necrosis factor alpha. Responses can be induced by killed Campylobacter as well as live bacteria and do not depend on the cytolethal distending toxin. C. jejuni infection of THP-1 cells triggers both nuclear translocation of functional NF-kappa B and stimulation of IL-1 alpha, indicating that NF-kappa B-dependent and -independent stimulation is occurring. The extent of proinflammatory cytokine stimulation suggests that monocytes might significantly contribute to intestinal inflammation and disease pathology.
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PMID:Induction of proinflammatory responses in the human monocytic cell line THP-1 by Campylobacter jejuni. 1270 37

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

Recognition of bacterial products by the innate immune system is dependent on pattern-recognition receptors: toll-like receptor 9 (TLR-9) in the case of bacterial DNA. We hypothesized that bacterial DNA can directly affect enteric epithelial cells. RT-PCR revealed constitutive TLR-9 mRNA expression in three human colonic epithelial cell lines (T84, HT-29, Caco-2) and THP-1 monocytes. Epithelial cells, in six-well culture plates or on filter supports, were exposed to E. coli DNA (1-50 microg/ml), synthetic CpG-rich oligonucleotides, or calf thymus DNA for 6-48 h. Exposure to E. coli DNA resulted in an increase in IL-8 mRNA, and a time- and dose-dependent increase in IL-8 secretion. Also, CpG oligonucleotides induced epithelial IL-8 production, whereas calf thymus DNA did not. Exposure to E. coli DNA resulted in phosphorylation of ERK 1/2 MAPK and inhibitors of ERK activity (PD98059, UO126) significantly reduced the evoked IL-8 production. In contrast, inhibitors of NFkappaB activity (PDTC, SN50) did not block E. coli DNA-induced IL-8 production. Electrophoretic mobility shift assays revealed that E. coli DNA stimulated epithelial AP-1 but not NFkappaB activation. The barrier (i.e., transepithelial resistance) and ion transport parameters of epithelial monolayers (assessed in Ussing chambers) were unaltered following E. coli DNA exposure. Thus model gut epithelia express TLR-9 mRNA and, while maintaining their barrier function, can respond to E. coli DNA by increased IL-8 production.
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PMID:Bacterial DNA evokes epithelial IL-8 production by a MAPK-dependent, NF-kappaB-independent pathway. 1283 93

One-week-old breast-fed miniature piglets were orally infected either with virulent LT2 strain or with a non-virulent SF1591 rough mutant of Salmonella Typhimurium for 1 d. Both microorganisms were cultivated from mesenteric lymph nodes but not from the blood of infected piglets. Interleukins (IL) 1 beta, 8, 18, tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were quantified by ELISA in plasma and washes of a terminal part of the small bowel. In plasma, cytokines were mostly missing in non-infected piglets and either missing or low in infected piglets. In the gut of non-infected piglets, IL-1 beta, IL-8 and IL-18 were detected whereas TNF-alpha and IFN-gamma were mostly missing. IFN-gamma levels highly increased (p < 0.05) after infection with nonvirulent salmonellae. The variability of cytokine levels in the gut of suckling piglets is discussed.
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PMID:Systemic and local cytokine response of young piglets to oral infection with Salmonella enterica serotype Typhimurium. 1287 55

Gastroesophageal reflux disease is the most common malady of the esophagus, affecting 7% of the United States population. Histological assessment demonstrates classic inflammatory mechanisms including selective leukocyte recruitment and hemorrhage, suggesting a prominent role for the microvasculature. We isolated and characterized human esophageal microvascular endothelial cells (EC) (HEMEC), examined inflammatory activation in response to cytokines, LPS, and acidic pH exposure, and identified signaling pathways that underlie activation. HEMEC displayed characteristic morphological and phenotypic features including acetylated LDL uptake. TNF-alpha/LPS activation of HEMEC resulted in upregulation of the cell adhesion molecules (CAM) ICAM-1, VCAM-1, E-selectin, and mucosal addressin CAM-1 (MAdCAM-1), increased IL-8 production, and enhanced leukocyte binding. Both acid and TNF-alpha/LPS activation lead to activation of SAPK/JNK in HEMEC that was linked to VCAM-1 expression and U-937 leukocyte adhesion. Expression of constitutive inducible nitric oxide synthase in HEMEC was in marked contrast to intestinal microvascular endothelial cells. In this study, we demonstrate that HEMECs are phenotypically and functionally distinct from lower gut-derived endothelial cells and will facilitate understanding of inflammatory mechanisms in esophageal inflammation.
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PMID:Isolation and characterization of human esophageal microvascular endothelial cells: mechanisms of inflammatory activation. 1291 42

Cells of the mucosal lining are the first to encounter invading bacteria during infection, and as such, they have developed numerous ways of detecting microbial intruders. Recently, we showed that epithelial cells recognize lipopolysaccharide (LPS) through the CD14-Toll-like receptor (TLR)-4 complex. Here, we identify the substructures of LPS that are recognized by the TLR4 receptor complex. In contrast to lipid A, the O-antigen does not mediate an inflammatory response; rather it interferes with the lipid A recognition. An Escherichia coli strain genetically modified to express penta-acylated lipid A not only showed reduced immunogenicity, but was also found to inhibit pro-inflammatory signalling induced by wild-type E. coli (hexa-acylated lipid A) as well as LPS from other bacteria of the Enterobacteriaceae family. Furthermore, penta-acylated LPS from Pseudomonas aeruginosa acted as an antagonist to hexa-acylated E. coli LPS, as did E. coli, as shown by its inhibitory effect on IL-8 production in stimulated cells. Hypo-acylated lipid A, such as that of P. aeruginosa, is found in several species within the gut microflora as well as in several bacteria causing chronic infections. Thus, our results suggest that the composition of the microflora may be important in modulating pro-inflammatory signalling in epithelial cells under normal as well as pathologic conditions.
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PMID:Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications. 1455 46

Several effects of bile acids (BAs) on colonic epithelial cells (CECs) have been described, including induction of proliferation and apoptosis. Some of these effects are mediated through activation of the NF-kappa B transcriptional system. In this study, we investigated the molecular mechanisms underlying the BA-induced gene expression in CECs. The human CEC line HT-29 and primary human CECs were treated with dilutions of salts of deoxycholic acid (DCA) and taurodeoxycholic acid (TDCA). NF-kappa B binding activity was analyzed with EMSA, RelA translocation with immunofluorescence, and I kappa B alpha- and RelA-phosphorylation with Western blot analysis. IL-8 mRNA and protein expression were assessed by quantitative PCR and ELISA. Functional impact of NF-kappa B activation was determined by blocking the proteasome activity with MG132 or by preventing IKK activity with a dominant-negative IKK beta delivered by adenoviral dominant-negative (dn) IKK beta (Ad5dnIKK beta). DCA and TDCA induced IL-8 expression in a dose- and time-dependent manner. It is interesting that DCA but not TDCA induced I kappa B alpha-phosphorylation, RelA translocation, and NF-kappa B binding activity. Accordingly, the proteasome inhibitor MG132 blocked DCA- but not TDCA-induced IL-8 gene expression. In contrast, TDCA-induced IL-8 gene expression correlated with enhanced RelA phosphorylation, which was blocked by Ad5dnIKK beta. Our data suggest that DCA-induced signal transduction mainly utilized the I kappa B degradation and RelA nuclear translocation pathway, whereas TDCA primarily induced IL-8 gene expression through RelA phosphorylation. These differences may have implications for the understanding of the pathophysiology of inflammation and carcinogenesis in the gut.
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PMID:Differential effects of deoxycholic acid and taurodeoxycholic acid on NF-kappa B signal transduction and IL-8 gene expression in colonic epithelial cells. 1472 7


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