title: Characterization of interleukin-1β in Helicobacter pylori-induced gastric inflammation and DNA methylation in interleukin-1 receptor type 1 knockout (IL-1R1(-/-)) mice.
abstract: Helicobacter pylori infection induced interleukin-1β (IL-1β) production and is associated with aberrant DNA methylation and gastric diseases. Here, we investigated the role of IL-1β in H. pylori-induced gastric inflammation and DNA methylation using IL-1 receptor type 1 knockout (IL-1R1(-/-)) mice, and compared the therapeutic efficacy of antimicrobial therapy with IL-1 receptor antagonist (IL-1ra). IL-1R1(-/-) and wild-type (WT) mice were infected with H. pylori for 16, 24 and 32 weeks. Infected WT mice at 24 weeks were given either antimicrobial therapy or IL-1ra. Comparing to the IL-1R1(-/-) mice, infected WT mice with functional IL-1β signaling had higher gastritis scores, higher IL-1β and iNOS mRNA expression, higher nitric oxide (NO) production and increased frequency of E-cadherin (E-cad) methylation at all the time points analyzed. IL-1β release was significantly elevated in infected WT mice than normal controls at 16 weeks post-infection (p<0.005). Treatment of infected mice with antimicrobial therapy and IL-1ra significantly reduced the degree of gastritis (p<0.005; p<0.05, respectively), iNOS expression (p<0.0001; p<0.01, respectively) and NO production (both p<0.001) compared with untreated controls. Mice receiving antimicrobial therapy had significantly lower IL-1β expression than untreated controls (p<0.0001). Both treatments reduced the incidence of E-cad methylation in infected mice compared with controls, however, no statistical significance was observed. There was no significant alteration of total DNA methyltransferase (DNMT) activity. These results demonstrated that IL-1β played a crucial role in H. pylori-induced gastric inflammation and DNA methylation. H. pylori eradication and IL-1ra administration could ameliorate inflammatory stress.
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Fung-Yu
authors.initials: FY
authors.lastname: Huang
authors.forename: Annie On-On
authors.initials: AO
authors.lastname: Chan
authors.forename: Regina Cheuk-Lam
authors.initials: RC
authors.lastname: Lo
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Danny Ka-Ho
authors.initials: DK
authors.lastname: Wong
authors.forename: Chi-Hin
authors.initials: CH
authors.lastname: Cho
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
authors.forename: Man-Fung
authors.initials: MF
authors.lastname: Yuen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation / Q000276:immunology*; D005756:Gastritis / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D015870:Gene Expression; D016481:Helicobacter Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000900:Anti-Bacterial Agents; D015820:Cadherins; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D053573:Receptors, Interleukin-1 Type I; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
keywords: DNA methylation; E-cadherin; Gastric cancer; Helicobacter pylori; Inflammation; Interleukin-1β; Nitric oxide