Mucosal IL-1β Research Articles

IL-1β and IL-8, matrix metalloproteinase 3, and pepsinogen secretion before and after H. pylori eradication in gastroduodenal phenotypes

Objective. Relations between host genetic factors and clinical outcomes of Helicobacter pylori infection are variable among ethnicities. The aim of this study was to examine gastric mucosal cytokines, matrix metalloproteinase 3 (MMP-3), and serum pepsinogen levels before and after eradication of H. pylori according to IL-1B genotypes and benign gastroduodenal phenotypes in a Korean population. Material and methods. A total of 349 Koreans including H. pylori-infected subjects (n=230) and H. pylori-negative controls (n=119) were enrolled. The former subjects were classified into groups according to the presence of non-atrophic gastritis (n=74), atrophic gastritis (n=56), gastric ulcer (n=37), and duodenal ulcer (n=63). IL-1B polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Gastric mucosal IL-1β, IL-8, and MMP-3, and serum pepsinogen I and II levels were measured by ELISA and radioimmunoassay, respectively. Results. There were no significant differences between the IL-1B–31/–511 haplotype (TT/CC, CT/CT, and CC/TT) frequencies among the H. pylori-positive and −negative groups. The genotypes of IL-1B–31/–511 polymorphisms did not affect clinical phenotypes, inflammatory cytokines, MMP-3, and pepsinogen secretion. Subjects with H. pylori-infected atrophic gastritis exhibited significantly higher basal levels of cytokines and a lower pepsinogen I/II ratio than those of other groups. Following H. pylori eradication, inflammatory cytokines significantly decreased and the pepsinogen I/II ratio increased in all groups. Conclusions. Mucosal inflammatory cytokines, MMP-3, and pepsinogen secretion are related to gastroduodenal phenotypes but not to IL-1B genotypes. Eradication of H. pylori can reduce mucosal inflammation and restore pepsinogen secretion.

IL-1β modulation of H,K-ATPase α-subunit gene transcription inHelicobacter pyloriinfection

Helicobacter pylori infection of the human gastric body induces hypochlorhydria by perturbing acid secretion. H. pylori inhibits parietal cell H,K-ATPase alpha-subunit (HKalpha) gene and protein expression, providing a mechanistic basis for clinical hypochlorhydria. Given that H. pylori infection increases gastric mucosal IL-1beta, an acid secretory inhibitor, we investigated the role of IL-1beta in H. pylori-mediated inhibition of HKalpha transcription. Human gastric adenocarcinoma (AGS) cells were transfected with promoter-reporter constructs containing human HKalpha 5'-flanking sequence deletions. IL-1beta (10 ng/ml) had no effect on the transcriptional activity of six progressively shorter deletion constructs of the HKalpha promoter (HKalpha2179-HKalpha340) and significantly stimulated the activity of HKalpha206, HKalpha177, HKalpha165, and HKalpha102 deletion constructs (80%, 100%, 46%, and 35%, respectively). H. pylori inhibited the transcriptional activity of HKalpha2179, HKalpha206, HKalpha177, and HKalpha165; IL-1beta relieved the H. pylori inhibition of HKalpha2179 and HKalpha206 activity but not HKalpha177 and HKalpha165 activity. AGS cell pretreatment with a MEK1/2 inhibitor prevented the IL-1beta-mediated stimulation, but p38 and JNK pathway inhibitors did not. IL-1beta mRNA levels in AGS cells were low and unaffected by H. pylori, and ELISAs of H. pylori-conditioned AGS culture media showed no measurable IL-1beta secretion. These data indicate that an IL-1beta-dependent cis-response element lies downstream of -206 nt in the HKalpha promoter and that IL-1beta-mediated upregulation of HKalpha transcription is affected by an ERK1/2 kinase signal pathway. We conclude that an IL-1beta-responsive HKalpha cis element positively regulates HKalpha gene transcription in shortened deletion constructs and that H. pylori-induced inhibition of HKalpha transcription is not mediated by IL-1beta.

Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial

Clarithromycin is postulated to possess immunomodulatory properties in addition to its antimicrobial activity. To evaluate the effect of clarithromycin on serum and nasopharyngeal cytokine and chemokine concentrations in children with an acute exacerbation of recurrent wheezing. Children with a history of recurrent wheezing or asthma and who presented with an acute exacerbation of wheezing were enrolled in a double-blind, randomized trial of clarithromycin vs placebo. Concentrations of tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, RANTES, eotaxin, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, and monocyte chemoattractant protein 1 were measured in serum and/or nasopharyngeal aspirates before, during, and after therapy. Mycoplasma pneumoniae and Chlamydophila pneumoniae infection were evaluated for by polymerase chain reaction and serologic testing. Nasopharyngeal concentrations of TNF-alpha, IL-1beta, and IL-10 were significantly and persistently lower in children treated with clarithromycin compared with placebo. There tended to be a greater effect of clarithromycin on nasopharyngeal cytokine concentrations in patients with evidence of M. pneumoniae or C. pneumoniae infection. No significant differences were detected in serum cytokines for children treated with clarithromycin compared with placebo. Clarithromycin therapy reduces mucosal TNF-alpha, IL-1beta, and IL-10 concentrations in children with an acute exacerbation of recurrent wheezing.

Relationship between IL-1β gene polymorphism and gastric mucosal IL-1β levels in patients with Helicobacter pylori infection

Interkeukin-1 (IL-1) gene cluster polymorphisms that are thought to enhance the production of IL-1beta are associated with an increased risk of gastric cancer. To determine the role of host genetic factors in Helicobacter pylori infection, we examined the relationship between gastric mucosal IL-1beta levels and IL-1B polymorphisms in patients with H. pylori infection. Biopsy tissues obtained from 99 patients were homogenized and gastric mucosal IL-1beta levels were measured by enzyme-linked immunosorbent assay (ELISA). Single-base polymorphisms at positions -511 and -31 in IL-1B were analyzed. The IL-1beta level in the antrum was significantly higher in genotype IL-1B-511C/C than in H. pylori-negative patients (P < 0.05). The IL-1B polymorphism did not influence the degree of gastric neutrophil and mononuclear cell infiltration, or gastric atrophy. IL-1beta levels in the corpus, but not those in the antrum, correlated to the severity of gastric atrophy. These findings indicate that IL-1B polymorphisms enhance IL-1beta production in the antrum; however, other factors might regulate the production of IL-1beta in the corpus of the stomach, regardless of IL-1B polymorphisms, and high IL-1beta production may be associated with the grade of gastric atrophy in the corpus mucosa in patients with H. pylori infection.

Gastric mucosal cytokine levels in relation to host interleukin-1 polymorphisms and Helicobacter pylori cagA genotype

ObjectiveThe outcome of a Helicobacter pylori infection is related in part to interrelationships among H. pylori virulence factors and the H. pylori-induced mucosal response. The host inflammatory response is partly governed by polymorphisms in pro-inflammatory genes.Material and methodsCytokine levels (interleukin (IL)-1β, IL-6 and IL-8) were examined in H. pylori-infected and uninfected normal-appearing mucosa from patients with non-ulcer dyspepsia (NUD), margins of gastric ulcers and cancer tissues. Cytokine levels were compared with cagA genotypes and host interleukin (IL)-1 polymorphisms.ResultsThe study comprised 168 Thai patients. All infected patients possessed anti-CagA antibody. Gastric mucosal IL-8 levels were significantly higher in H. pylori-positive cases than in -negative cases in all three tissue types (e.g. 1115 versus 217 pg/mg protein for NUD) (p<0.001). Normal-appearing but H. pylori-infected antral mucosa of patients with cagA type 1a strains had higher IL-8 levels than those with type 2a strains (2632 versus 1036 pg/mg protein) (p<0.005). IL-1B-511T/T carriers had higher antral mucosal IL-1β levels versus non-carriers (pg/mg protein) (T/T=221, T/C=178, C/C=70) (p=0.005). IL-1B-511T/T carriers also had higher IL-1β levels versus non-carriers in H. pylori-negative patients.ConclusionsIt was found that both the host factors (IL-1 polymorphisms) and bacterial factors (cagA type 1a versus type 2a) influenced gastric mucosal cytokine levels. Future studies should concentrate on interactions among host factors (e.g. genetics and tissue responses) and bacterial and environmental factors.

Dietary rutin, but not its aglycone quercetin, ameliorates dextran sulfate sodium-induced experimental colitis in mice: attenuation of pro-inflammatory gene expression

Oxidative stress has been shown to play a pivotal role in the onset of inflammatory bowel disease (IBD) and carcinogenesis. We evaluated the effects of two dietary anti-oxidants, rutin and its aglycone quercetin, on dextran sulfate sodium (DSS)-induced experimental colitis in mice. Female ICR mice were fed a diet containing 0.1% rutin or 0.1% quercetin for 2 weeks, and given 5% DSS in drinking water during the second week to induce colitis. We also examined the dose-dependency of rutin and quercetin (0.01% and 0.001% each) as well as their therapeutic efficacy, which was evaluated following DSS administration, on DSS-induced colitis. The protein level of interleukin (IL)-1β in both colonic mucosa and peritoneal macrophages was quantified by enzyme-linked immunosorbent assay. Further, mRNA expression levels of IL-1β, tumor necrosis factor-α, IL-6, granulocyte macrophage-colony stimulating factor, inducible nitric oxide synthase, and cyclooxygenase (COX)-1 and COX-2 in colonic mucosa were determined by reverse transcription-polymerase chain reaction. A diet containing 0.1% rutin, but not quercetin, attenuated DSS-induced body weight loss and shortening of the colorectum ( P < 0.01 and <0.05, respectively), and dramatically improved colitis histological scores. Further, DSS-induced increases in colonic mucosal IL-1β levels were blunted significantly in rutin-, but not quercetin-, fed mice ( P < 0.01), while dietary rutin attenuated the expressions of IL-1β and IL-6 mRNA in colonic mucosa (each, P < 0.01). As for dose dependency, 0.01%, but not 0.001%, dietary rutin significantly reduced mucosal IL-1β levels ( P < 0.01). Notably, a 0.1% rutin diet given 3 days after DSS treatment significantly suppressed both colorectal shortening and IL-1β production ( P < 0.05 and <0.01, respectively). Dietary rutin ameliorates DSS-induced colitis, presumably by suppressing the induction of pro-inflammatory cytokines. Our results suggest that rutin may be useful for the prevention and treatment of IBD and colorectal carcinogenesis via attenuation of pro-inflammatory cytokine production.

Host and microbial constituents influence helicobacter pylori-induced cancer in a murine model of hypergastrinemia

Background & Aims: Helicobacter pylori cag + strains and high-expression host interleukin 1β (IL-1β) polymorphisms augment the risk for intestinal-type gastric adenocarcinoma, a malignancy that predominates in males. We examined the effects of an H. pylori cancer-associated determinant ( cagE), IL-1β, and host gender in a transgenic hypergastrinemic (INS-GAS) murine model of gastric carcinogenesis. Methods: Male and female INS-GAS mice infected with wild-type H. pylori, an H. pylori cagE − mutant, or H. felis were killed 2–24 weeks postchallenge. Gastric injury was scored from 0 to 4, and mucosal IL-1β levels were quantified by ELISA. Results: Male INS-GAS mice infected with H. pylori uniformly developed atrophy, intestinal metaplasia, and dysplasia by 6 weeks and carcinoma by 24 weeks. Mucosal IL-1β concentrations increased 12 weeks following Helicobacter challenge, but levels then decreased by 24 weeks. Inactivation of cagE delayed the progression to carcinoma, but neoplasia ultimately developed in all males infected with the H. pylori mutant. In contrast, none of the H. pylori-infected female mice developed cancer, and injury scores, but not IL-1β levels, were significantly higher in males compared with females. Conclusions: H. pylori infection induces gastric adenocarcinoma in an experimental mouse model of disease. Cancer is restricted to males and loss of cagE temporally retards but does not abrogate pathologic progression. Mucosal levels of IL-1β increase prior to the development of gastric cancer but are not related to gender. The INS-GAS model is effective for investigating discrete host-microbial interactions that culminate in gastric cancer within the context of biologic conditions induced by H. pylori.

Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1β production in Helicobacter pylori infection

Background & Aims: Although epidemiological studies suggest that interleukin (IL)-1 genetic polymorphisms are involved in Helicobacter pylori–related gastric carcinogenesis, the data are conflicting regarding the effects of these polymorphisms on IL-1β production. Methods: IL-1B-511 polymorphism was genotyped by polymerase chain reaction (PCR)–restriction fragment length polymorphism, and IL-1RN variable number of tandem repeats was determined by PCR. Mucosal IL-1β levels were measured by enzyme-linked immunosorbent assay. To determine which factors influence mucosal IL-1β levels, gastric inflammation, and atrophy, multiple regression analyses were performed. Results: We studied 117 H. pylori–infected Japanese patients. Carriers of the IL-1B-511T/T genotype or IL-1RN*2 allele had higher mucosal IL-1β levels than noncarriers (partial regression coefficient [PRC] ± SE), TT versus CC: 37.6 ± 6 [antrum] and 32.1 ± 6 [corpus] pg/mg protein (P < 0.001 for each), *1/*2 versus *1/*1: 24 ± 8 [antrum] (P <0.01) and 36.5 ± 7 [corpus] (P <0.001). Simultaneous carriers of IL-1B-511T/T genotype and IL-1RN*2 allele had the highest IL-1β levels (82.9 ± 12 [antrum] and 87.2 ± 11 [corpus]) and showed a synergistic effect between 2 loci. The *1/*2 carriers were closely related to atrophy (PRC ± SE; 0.87 ± 0.4 [antrum] and 0.93 ± 0.4 [corpus], P < 0.05), whereas being a carrier of the -511T/T genotype was related to severe gastric inflammation. Conclusions: IL-1 genetic polymorphisms influenced H. pylori–related gastric mucosal IL-1β levels and were related to gastric inflammation and atrophy, factors thought to be important in gastric carcinogenesis.GASTROENTEROLOGY 2002;123:1793-1803

Association of IL-1-β gene polymorphism with gastric mucosal IL-1β and IL-8 levels in patients with Helicobacter pylori infection

Association of IL-1-β gene polymorphism with gastric mucosal IL-1β and IL-8 levels in patients with Helicobacter pylori infection

Association of IL-1-β gene polymorphism with gastric mucosal IL-1β and IL-8 levels in patients with Helicobacter pylori infection

Association of IL-1-β gene polymorphism with gastric mucosal IL-1β and IL-8 levels in patients with Helicobacter pylori infection

Helicobacter felis infection is associated with lymphoid follicular hyperplasia and mild gastritis but normal gastric secretory function in cats.

The relationship of Helicobacter felis, a bacterium observed in the stomachs of cats, to gastric disease is unclear. The objective of this study was to determine if H. felis infection alters gastric histopathology, proinflammatory cytokine expression, and secretory function and evokes a humoral immune response in cats. Five specific-pathogen-free (SPF) Helicobacter-free cats were studied before and for 1 year after oral inoculation with H. felis (ATCC 49179). Four SPF H. felis-uninfected cats served as controls. The stomachs of all five H. felis-inoculated cats became colonized, as determined by urease activity, histopathology, PCR, culture, and transmission electron microscopy of serial gastric biopsies at 0, 3, 5, 8, and 12 months. Uninoculated cats remained Helicobacter free. Lymphoid follicular hyperplasia, atrophy, and fibrosis were observed primarily in the pylorus of infected cats. Mild mononuclear inflammation was detected in both infected and uninfected cats, but was more extensive in infected cats, with pangastric inflammation, eosinophilic infiltrates, and cardia gastritis observed only in infected cats. No upregulation of antral mucosal interleukin 1alpha (IL-1alpha), IL-1beta, or tumor necrosis factor alpha was detected by reverse transcription-PCR in any cat. The gastric secretory axes, assessed by fasting plasma gastrin, antral mucosal gastrin and somatostatin immunoreactivity, and pentagastrin-stimulated gastric acid secretion, were similar in both infected and uninfected cats. Gradual seroconversion (immunoglobulin G) was observed in four of five infected cats, with enzyme-linked immunosorbent assay values reaching 4x to 12x baseline 12 months postinfection. These findings indicate that H. felis infection in cats induces lymphoid follicular hyperplasia, mild gastritis, and seroconversion, but is associated with normal gastric secretory function.

Relation between clinical presentation,Helicobacter pylori density, interleukin 1β and 8 production, and cagA status

BACKGROUNDIt is not known whethercagA+ Helicobacter pylori in duodenal ulcer (DU) have enhanced virulence compared with non-DU cagA+ H pylori.AIMSTo investigate the relation between presentation, H pylori density, interleukin 1β...

IL1 β gene Allele 2 involves the decreased production of gastric mucosal IL1β in response to Helicobacter pylori of common genetic strain in Japan, and relates to the pathogenesis of duodenal ulcer

IL1 β gene Allele 2 involves the decreased production of gastric mucosal IL1β in response to Helicobacter pylori of common genetic strain in Japan, and relates to the pathogenesis of duodenal ulcer