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)

Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable/fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacter pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NFkappaB signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NFkappaB and TRAF6-MAP3K7-AP-1 signaling cascades in epithelial and immune cells through lipopolysaccharide recognition by TLR2 or TLR4. IL-1beta, IL-6, IL-8, TNFalpha and IFNgamma are elevated in gastric mucosa with Helicobacter pylori infection. IL-6 and TNFalpha induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF, RhoA, JNK, PKC, NFAT, and NLK signaling cascades. WNT-beta-catenin-TCF/LEF signaling induces upregulation of MYC, CCND1, WISP1, FGF20, JAG1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NFkappaB signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC, and NFAT signaling cascades. Helicobacter pylori infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch signaling, while DKK1 and SFRP1 inhibit WNT signaling. Stem cell signaling network, consisting of WNT, Notch, FGF, Hedgehog and BMP signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell signaling network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell signaling molecules could be utilized for the personalized medicine.
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PMID:Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. 1756 83

The innate immune response to Helicobacter pylori infection is beginning to be understood and recent works support a role for Toll-like receptors (TLRs). Our aim was to study the response of human neutrophils to H. pylori and to elucidate the role of TLR2 and TLR4. Neutrophils from healthy H. pylori-negative volunteers were cocultured with H. pylori 26695 strain. The release of IL-8, IL-1beta, tumor necrosis factor (TNF)-alpha and IL-10 was measured. The role of TLR2 and TLR4 was investigated with blocking assays using monoclonal antibodies against TLRs. Neutrophils produced a significant increase of IL-8, IL-1beta and TNF-alpha after 3, 6 and 24 h of H. pylori challenge, respectively, whereas IL-10 increased after 24 h. Helicobacter pylori challenge increased TLR2 and TLR4 expression; and antibodies against TLR2 and TLR4 diminished significantly the H. pylori-induced production of IL-8 and IL-10. In human neutrophils, H. pylori induces an early inflammatory response, partially mediated via TLR2 and TLR4 activation.
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PMID:Activation of human neutrophils with Helicobacter pylori and the role of Toll-like receptors 2 and 4 in the response. 1789 76

Selective inhibition of proinflammatory chemokines such as IL-8 is an important approach to combat inflammatory and infection diseases. Previous studies suggested that interaction of transcription factors NFkappaB repressing factor (NRF) and NFkappaB play a crucial role in activation of IL-8 gene expression. In a search for a specific inhibitor of IL-8 expression, we applied tandem affinity purification to investigate interaction of NRF and NFkappaB p65 in cells. We identified a synthetic peptide corresponding to aa 223-238 of NRF interfering with binding of endogenous p65 to NRF. Furthermore, nucleofection experiments were established to introduce this inhibitory peptide into the nucleus of IL-1 stimulated human cervical and Helicobacter pylori infected gastric epithelial cells. Our data clearly show that the specific peptide disturbing NRF/NFkappaB interaction is able to significantly decrease endogenous IL-8 gene transcription in response to IL-1 or Helicobacter pylori infection. Thus, our study provides novel insights into NRF and NFkappaB interaction in vivo and may facilitate the design of new anti-IL-8 drugs based on novel strategies.
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PMID:Peptide-mediated disruption of NFkappaB/NRF interaction inhibits IL-8 gene activation by IL-1 or Helicobacter pylori. 1802 6

Earlier studies have shown that the antral immune response in Helicobacter pylori infection has a mixed Th1-Th2-T-regulatory profile. After eradication, a chronic inflammation remains in some patients, but a follow-up study with a comprehensive cytokine profile in has not previously been published. Twelve patients with H. pylori positive peptic ulcer disease (five antral and seven duodenal) were enrolled and cytokine gene expressions in antral biopsies were determined (1) at entry, (2) after resolving the ulcer with proton pump inhibitor (PPI) treatment and (3) after eradication. The second endoscopy was performed 4 weeks after ending the PPI treatment, and the third endoscopy was performed after a mean of 10 months after eradication. Inflammation was graded according to the updated Sydney system. Interleukin (IL)1beta, IL8, IL12A, IL18, TNFalpha, IFNgamma, IL4, IL6 and IL10 expression levels were analysed by real-time RT-PCR. Mixed mononuclear and neutrophil infiltrates were seen at entry and after ulcer healing. After eradication, low-grade mononuclear infiltrates were found. The cytokine expression levels after ulcer healing (H. pylori positive gastritis) were not significantly different from the levels at entry (ulcer). After eradication, attenuation of the Th1 cytokines except for TNFalpha and a persisting increase of IL4 levels were observed, whereas the IL10 expression was markedly reduced. The present data did not indicate a specific ulcer promoting cytokine gene regulation profile. However, after eradication a chronic low-grade inflammation was seen with reduced Th1, prolonged Th2 and disappearance of the T-regulatory response.
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PMID:Alterations in antral cytokine gene expression in peptic ulcer patients during ulcer healing and after Helicobacter pylori eradication. 1802 89

Helicobacter pylori infection is the most common cause of gastritis, gastric ulcer and adenocarcinoma. It has proven difficult to cure because of its capability to develop strains resistant to antibiotics. The effect of three strains of lactic acid bacteria (LAB) and bovine colostral preparations on the adhesion of H. pylori NCTC 11637 on gastric adenocarcinoma (AGS) cells and on the interleukin (IL)-8 production was studied. Before infection, H. pylori were pretreated with Lactobacillus plantarum MLBPL1, Lactobacillus rhamnosus GG, Lactococcus lactis, or with a colostral preparation with or without specific H. pylori antibodies. The relative number of H. pylori adhered on AGS cells was determined by urease test. IL-8 produced by the cells was studied by enzyme-linked immunosorbent assay. Colostral preparations with and without specific antibodies reduced the adhesion of H. pylori on AGS cells in a dose-dependent manner. Live LAB at a concentration of 10(10) CFU/ml reduced the adhesion by approximately 50% (P < 0.05). After the infection of AGS cells by H. pylori, the IL-8 level rose up to about 10-fold (5500 +/- 1600 pg/ml). Pretreatment of H. pylori with colostral preparations or high concentrations of LAB prevented this IL-8 rise. Similar effect was seen with live and heat-killed LAB, the live LAB being more effective. Heat-killed LAB at a concentration of 10(10) CFU/ml rose the IL-8 level of non-infected cells significantly. Suppression of IL-8 production by LAB or colostral products could have a suppressive effect on inflammation in Helicobacter infection.
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PMID:Effect of specific colostral antibodies and selected lactobacilli on the adhesion of Helicobacter pylori on AGS cells and the Helicobacter-induced IL-8 production. 1862 49

The cure rates of Helicobacter pylori infection by using a combination of a proton pump inhibitor (PPI) and antimicrobial agents are mainly influenced by bacterial susceptibility to antimicrobial agents and the magnitude of acid inhibition during the treatment. Currently used empirical triple therapies do not reliably produce a > or =80% cure rate on an intention-to-treat basis. Therefore, tailored regimens based on relevant microbiological findings and pharmacogenomics are recommended for attaining an acceptable > or =95% cure rate. Recently, virulence factors of H. pylori, such as cagA and vacA, are reported to be major factors determining the cure rates. Individuals infected with strains with cagA-negative and vacA s2 genotypes have significantly increased risk of eradication failure of H. pylori infection. These virulence factors enhance gastric mucosal inflammation and are associated with the development of peptic ulcer and gastric cancer. H. pylori virulence factors induce proinflammatory cytokines, such as interleukin (IL)-1, IL-8, and tumor necrosis factor (TNF)- which influence mucosal inflammation and/or gastric acid secretion. When physicians select an H. pylori eradication regimen with an acceptable cure rate, they might need to consider H. pylori virulence factors, especially cagA and vacA.
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PMID:Virulence factor genotypes of Helicobacter pylori affect cure rates of eradication therapy. 1921 27

Previous studies suggested the relationship between interleukin (IL)-8 -251 A/T gene polymorphism and risk of gastric cancer (GC). However, the currently available results were not consistent. The present study aimed to quantitatively analyse this association using a meta-analysis. Published literature from PubMed, EMBASE and CNKI (China Knowledge Resource Integrated Database) were retrieved. Twelve case-control studies with 3012 cases of GC and 3893 controls were included. Overall, IL-8 -251 A/T polymorphism was not associated with the risk of GC. However, when stratified for ethnicity/country, the results showed that A allele carriers had an increased risk of GC while T allele carriers had a decreased risk of GC in Korean people. When stratified for Helicobacter pylori infection, the results showed that A allele carriers with H. pylori infection had an increased risk of GC while T allele carriers with or without H. pylori infection had a decreased risk of GC. When stratified for tumor location and histological type (Lauren's classification), A allele carriers had an increased risk of intestinal- and diffuse-type of GC and non-cardia cancer, while T allele carriers had a decreased risk of intestinal- and diffuse-type of GC and non-cardia cancer. These results suggest that overall IL-8 -251 A/T gene polymorphism is not associated with the risk of GC and the association may be varied according to histological type, tumor location, H. pylori infection and ethnicity/country. More well-designed studies based on larger population are needed to confirm our results and further evaluate the association between IL-8 -251 A/T gene polymorphism and gastric cancer.
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PMID:Interleukin-8 -251 A/T gene polymorphism and gastric cancer susceptibility: a meta-analysis of epidemiological studies. 2036 44

Helicobacter pylori infection can induce aberrant CpG island hypermethylation in gastric mucosal epithelial cells. Single nucleotide polymorphisms of proinflammatory cytokine genes encoding for interleukin 1B (IL1B), IL6, and IL8 have been demonstrated to be associated with an increased risk of gastric cancer. To identify the influence of host genetic factors in CpG island hypermethylation induced by H. pylori infection, we analyzed H. pylori-infected chronic gastritis (n = 111) and gastric cancer samples (n = 78) for the methylation status of eight genes previously shown to be hypermethylated in chronic gastritis and single nucleotide polymorphisms of IL1B, IL6, and IL8. The methylation levels were then compared between different genotypes. Gastric cancers from patients with the IL1B-511T/T allele showed significantly higher methylation levels in five genes as compared with gastric cancers from IL1B-511 C carriers (P < 0.05). An increased level of hypermethylation in association with the IL1B-511T/T allele was observed in chronic gastritis samples, but the association was not statistically significant. These findings suggest that the IL1B-511T/T allele is associated with enhanced hypermethylation of multiple CpG island loci, which might contribute to an increase in the risk for gastric cancer in individuals with H. pylori infection and IL1B-511T/T allele.
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PMID:Influence of IL1B polymorphism on CpG island hypermethylation in Helicobacter pylori-infected gastric cancer. 2040 97

Helicobacter pylori infection of the lining of the stomach induces an array of inflammatory cytokine production leading to gastritis and peptic ulcer disease. The aim of this study was to investigate the effect of curcumin on the production of interleukin (IL)-8, IL-1beta, tumor necrosis factor (TNF)-alpha and cyclooxygenase (COX)-2 in gastric mucosa from H. pylori-infected gastritis patients. Patients were randomly assigned to receive either OAM (Omeprazole, Amoxicillin and Metronidazole) treatment or a course of curcumin. Gastric biopsies were collected before and after treatment and were examined for the level of inflammatory cytokines mRNA by semi-quantitative reverse transcription polymerase chain reaction. The eradication rate of H. pylori in patients that received OAM treatment was significantly higher than the patients that received curcumin (78.9% versus 5.9%). The levels of IL-8 mRNA expression in the OAM group significantly decreased after treatment, but no changes of other cytokines were found. This emphasizes an important role of IL-8 in H. pylori infection. The decreases of cytokine production were not found in the curcumin group. We concluded that curcumin alone may have limited anti-bactericidal effect on H. pylori, and on the production of inflammatory cytokines. Nevertheless, other studies have reported that patients treated with curcumin had relieved symptoms. Further investigation should be carried out as the use of curcumin in combination with therapeutic regimens may be beneficial as an alternative treatment.
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PMID:Investigation of the anti-inflammatory effect of Curcuma longa in Helicobacter pylori-infected patients. 2043 67

Identification of biomarkers is needed for development of screening programs to prevent gastric cancer. Because racial differences exist in cancer rates, we aimed to evaluate the association between polymorphisms in inflammation-related genes and gastric preneoplastic lesions in African Americans and Caucasians from Louisiana, USA. Gastric biopsies from 569 adults (361 African Americans and 208 Caucasians) undergoing diagnostic endoscopy were used for histological diagnosis and genomic DNA extraction. Polymorphisms within eight genes (IL1B, IL8, IL6, TNF, PTGS2, ARG1, IL10 and TGFB1) were investigated by TaqMan. The cagA status of Helicobacter pylori infection was assessed by PCR. Haplotype logistic regression models were used to identify variables associated with intestinal metaplasia or dysplasia. African Americans carrying the haplotype IL1B-511T/-31C/+3954T, which includes the three risk-associated alleles at the IL1B locus, were more likely to being diagnosed with intestinal metaplasia or dysplasia than those carrying the most common haplotype T-C-C (adjusted OR: 2.51, 95% CI: 1.1-5.5). None of the polymorphisms were associated with intestinal metaplasia and dysplasia in Caucasians. Age and cagA-positive status were independent factors associated with these lesions. Haplotypes at the IL1B locus may participate in mediating the susceptibility to gastric carcinogenesis and might be useful as markers of advanced premalignant lesions in African Americans. Interestingly, carriage of IL1B+3954T allele seems to be the key factor, even though the role played by other polymorphisms cannot be excluded.
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PMID:Association of haplotypes of inflammation-related genes with gastric preneoplastic lesions in African Americans and Caucasians. 2047 75


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